4H-S-Triazolo[4,3-2][1,5]benzodiazepin-5-ones

ABSTRACT

Compounds of the following formula   &lt;IMAGE&gt;   are useful as central nervous system depressants, tranquilizers, sedatives, growth promotors, anti-convulsants and muscle relaxants in mammalian species.

RELATED APPLICATION

This is a divisional application of application Ser. No. 365,012 as filed May 29, 1973, now abandoned.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide new compounds which are useful as central nervous system depressants, tranquilizers and sedatives. Another object is to provide methods for the preparation of these compounds. Another object is to provide compositions for the administration of the compounds of the invention. These and other objects of the present invention will be apparent from the following description.

SUMMARY OF THE INVENTION

It has now been found that 4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-ones of the following formula ##STR2## ARE USEFUL CNS depressants, tranquilizers, sedatives, growth promotors, anti-convulsants and muscle relaxants in mammalian species.

DETAILED DESCRIPTION

The novel 4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-ones of formula 1 are useful CNS depressants, tranquilizers and sedatives. The novel compounds of formulas 3-12, and the compounds of formulas 13 and 14 some of which are also novel, are intermediates for the compounds of formula 1. ##STR3## In the foregoing formulas

R¹ is H; phenyl; X-substituted phenyl wherein X is as defined below; 2-, 3- or 4-pyridyl, cycloalkyl of 3-5 carbons, alkyl of 1-4 carbons optionally substituted by amino, by monoalkylamino of 1-4 carbons, by di-alkylamino of 1-4 carbons, by nitro, by cyano, by hydroxy, by alkoxy of 1-4 carbons, by alkanoyloxy of 1-4 carbons, by phenyl wherein the phenyl ring is optionally substituted by one or more X groups wherein X is as defined below, or by a cyclic imine of formula ##STR4## where D is methylene, oxygen or N-R¹⁰ and where p and q may be the same or different and are the integers 1, 2, and 3 provided that p + q is at least 1;

R² is H; alkyl of 1-4 carbons optionally substituted by amino, mono-lower alkyl, di-lower alkyl amino, cyclic imines of formula ##STR5## where the cyclic imine is as defined above; hydroxy; alkoxy of 1-6 carbons or ##STR6## where ##STR7## is an acyl group capable of removal and replacement by hydrogen or alkyl of 1-4 carbons and R⁵ is alkyl of 1-5 carbons optionally substituted by phenyl or X-substituted phenyl; or R⁵ is phenyl optionally substituted by 1 or more X-substituents

X and Y can be the same or different and are hydrogen, F, Cl, Br, trifluomethyl, alkyl of from 1-6 carbons, alkoxy of from 1-6 carbons, nitro, cyano, amino, alkanoylamino of 1-4 carbons, alkylthio of 1-6 carbons, alkylsulfinyl of 1-6 carbons or alkyl sulfonyl of 1-6 carbons;

R³ is alkyl of from 1-6 carbons, benzyl or phenethyl;

R⁴ is t-butyl or benzyl optionally substituted on the phenyl ring by one to three X groups;

R⁸ is alkyl of from 1-6 carbons, or phenyl optionally substituted by any alkyl, aralkyl or aryl radical compatible with cyclization to form a 7-membered ring;

R⁹ is hydrogen or alkyl of from 1-4 carbons;

n is 0, 1 or 2; m is 0 or 1;

R¹⁰ is hydrogen, alkyl of 1-4 carbons or phenyl optionally substituted by X;

T is halogen, preferably chlorine, bromine or iodine.

R¹¹ is hydrogen or alkyl of 1-4 carbons;

R¹² is alkyl of 1-4 carbons substituted by the groups ##STR8## where P and Q may be the same or different and may be hydrogen, phenyl, X-substituted phenyl, naphthyl or X-substituted naphthyl, with the proviso that at least one of P and Q is one of the foregoing aryl radicals,

R¹³ is alkyl of 1-6 carbons.

Preferably, R¹ is hydrogen, cycloalkyl of 3-5 carbons, or alkyl of 1-4 carbons optionally substituted by amino, nitro, cyano, hydroxy, alkoxy of 1-4 carbons, alkanoyloxy of 1-4 carbons, mono-alkylamino of 1-4 carbons, dialkylamino of 1-4 carbons or by a cyclic imine of formula ##STR9## where D, p and q are as previously defined. Most preferably, R¹ is hydrogen or alkyl of 1-4 carbons.

Preferably, R² is hydrogen, alkyl of 1-4 carbons or hydroxy.

Preferably, R⁸ is alkyl of 1-4 carbons. The radical R⁸ as well as the oxygen atom to which it is bonded are removed during cyclization.

Synthesis

The 4-H-s-triazolo[4,3-a][1,5]benzodiazepin-5-ones of formulas 1 and 11 can be prepared by several methods.

One method (hereinafter called the first method) involves reacting a compound of formulas 3-6 with from about 0.8 to about 6.0, preferably from about 1.0 to about 3.0 molar equivalents of an acid hydrazide of formula ##STR10## (where R¹ is as defined previously) in an inert, organic solvent or mixture of solvents. Typical organic solvents which may be used in the above reaction include aryl hydrocarbons, e.g., benzene, toluene, xylene and the like; chlorinated hydrocarbons such as di-, tri-, tetrachloroethanes and the like; lower molecular weight alkanols of 1-6 carbons such as methanol, ethanol, tertiary butyl alcohol, n-butanol and the like; N,N-dialkylformamides, N,N-dialkyl alkanoyl amides wherein the alkyl and alkanoyl radicals have 1-4 carbons, such as dimethylformamide, dimethylacetamide and the like; hexamethylphosphorous triamide, ethers, such as dioxane and the like and di-lower alkyl sulfoxides, such as dimethyl sulfoxide and the like. The reaction is carried out at from about 40° C to about 250° C, preferably from about 60° C to about 180° C, until a significant amount of end product is obtained, typically, for from about 1/4 to about 92 hours, preferably from about 1 to about 48 hours.

The final product of formula 1 or 11 is isolated by conventional techniques. For example, the reaction mixture is evaporated and the residue is partitioned between aqueous sodium bicarbonate and a water-immiscible inert, organic solvent, such as halogenated hydrocarbons, e.g., methylene chloride, chloroform or trichloroethylene; alkyl esters wherein both the acid and alcohol from which the ester is derived may have from 1 to 4 carbon atoms, e.g., ethyl acetate, propyl acetate, ethyl propionate and the like. The organic solvent is washed with water, dried and chromatographed.

A compound of formula 12 may be converted to the corresponding compound of formula 1 by another method for the synthesis of compounds of formula 1 where R¹ is alkyl substituted by amino, mono-alkyl amino or a hydroxy group. Such a method involves reacting a compound of formula 12 with appropriate reagents under appropriate conditions as described below suitable for the selective replacement of the ##STR11## or the ##STR12## by a hydrogen atom.

One such method involves reacting the compounds of formula 12 with at least about 0.5 preferably at least about 0.8, molar equivalent of an inorganic hydrogen halide (preferably hydrogen chloride, hydrogen bromide and hydrogen fluoride) or with a halogenated lower alkyl carboxylic acid (preferably trifluoroacetic acid). The reaction is run in anhydrous hydrogen fluoride, or, when employing other acids, in an optional inert solvent.

Typical solvents include lower carboxylic acid such as acetic acid and the like; ethers such as diethyl ether, dioxane, tetrahydrofuran and the like; lower molecular weight alkanols of 1-6 carbons such as methanol, ethanol, and the like; alkyl esters wherein both the acid and the alcohol from which the ester is derived may have from 1-4 carbon atoms such as ethyl acetate, propyl acetate, ethyl propionate and the like; halogenated hydrocarbons such as methylene chloride, chloroform, di-, tri- and tetrachloroethanes and the like; nitroalkanes of 1-4 carbons such as nitromethane, nitroethane and the like; or lower alkyl ketones of 2-5 carbons such as acetone, methylethyl ketone and the like.

The reaction is carried out at from about -50° C to about 200° C, preferably from about 0° C to about 120° C, until a significant amount of end product is obtained, typically, for from about 1/10 to about 92, preferably from about 1/6 to about 30 hours. The corresponding product of formula 1 is isolated by conventional techniques. For example, with all acids except hydrogen fluoride, the reaction mixture is diluted with an inert water-immiscible organic solvent, washed with dilute aqueous sodium bicarbonate, dried and chromatographed. When using hydrogen fluoride, the hydrogen fluoride is evaporated, the residue dissolved in an inert organic solvent, such as halogenated hydrocarbons, e.g., methylene chloride, chloroform or trichloroethylene; alkyl esters wherein both the acid and the alcohol from which the ester is derived may have from 1-4 carbon atoms, e.g., ethylacetate, propyl acetate, ethyl propionate and the like, washed with water, dried and chromatographed.

Another such method for the selective replacement of the ##STR13## by hydrogen is compounds of formula 12 involves the reaction of said compounds of formula 12 with hydrogen in the presence of an appropriate catalyst, in an inert organic solvent. Typical catalysts include platinum, Raney nickle and, preferably, palladium. Typical solvents include lower alkanols of 1-6 carbons such as ethanol, methanol, and the like; formic acid; lower alkanoic acids of 2-5 such as acetic acid and the like as well as other typical solvents well known to those versed in the art. Typical hydrogenation pressures are from about 0.1 to about 2000 atmospheres, preferably from about 0.8 to about 100 atmospheres. The reactions are carried out for from about 1/2 to about 96 hours, preferably from about 1 to about 72 hours at from about 0° C to about 200° C, preferably from about 20° C to about 120° C. The products are isolated in a conventional manner. For example the catalyst is filtered off, the solvent evaporated and the product chromatographed.

Another method for the synthesis of compounds of formulas 1 and 11 involves heating compounds of formula 7 either alone or in an inert, organic solvent at from about 60° C to about 350° C, preferably from about 80° C to about 300° C for about 1/2 to about 72 hours, preferably from about 1 to about 24 hours. Typical inert, organic solvents that are used are those defined in the first method. The products are isolated by conventional techniques. For example, the reaction is diluted with a water-immiscible inert, organic solvent, washed with water dried and chromatographed.

Another method (hereinafter called the fifth method) of synthesis for compounds of formulas 1 and 11 involves reacting compounds of formula 8 with from about 0.8 to about 6, preferably from about 1 to about 3, molar equivalents of acyl derivatives of formula ##STR14## in an optional inert organic solvent. Typical inert organic solvents which may be used includes aryl hyrocarbons such as benzene, toluene, xylene and the like; chlorinated hydrocarbons such as tri- and tetrachloroethanes and the like; ethers such as 1,2dimethoxyethane tetrahydrofuran, dioxane and the like; N,N-dialkylformamides and alkyl alkanoylamides wherein the alkyl and alkanoyl radicals have 1-4 carbons such as dimethylformamide, dimethylacetamide and the like. Where W is lower alkoxy or hydroxy, suitable solvents also include lower alkanols of 1-6 carbons such as ethanol, t-butyl alcohol and n-butyl alcohol and the liked and dimethyl sulfoxide. The reaction conditions and the isolation of the products are as described in the first method.

Another method for the synthesis of compounds of formulas 1 and 11 involve reacting compounds of formula 9 with at least about 0.1 preferably from at least about 0.8 to about 3 molar equivalents of an acyl derivative of formula ##STR15## in the presence of at least about 0.1, preferably from at least about 0.8 to about 3, molar equivalents of an inorganic hydrohalic acid, preferably hydrogen bromide or hydrogen chloride. The reaction can optionally be run in an inert organic solvent. Where compounds of formula ##STR16## are "strong" carboxylic acids, such as chloroacetic, trifluoroacetic and oxalic acid and the like, the use of a hydrohalic acid is optional. Typical inert organic solvents include lower molecular weight ethers such as 1,2 -dimethoxyethane, dioxane, tetrahydrofuran and the like; halogenated hydrocarbons such as methylene chloride, di-, tri-, and tetrachloroethane and the like; nitroalkanes of 1-4 carbons such as nitromethane, nitroethane and the like; lower alkanols of 1-6 such as ethanol, n-butanol and the like. The reaction is carried out at from about -50° C to about 250° C, preferably from about +10 to about 180° C, for from about 1/4 to about 96 hours, preferably from about 1/2 to about 48 hours. The products are isolated using conventional techniques as described in the first method.

Compounds of formula 1 where R¹ is lower acyloxy ##STR17## can be prepared by reacting compounds of formula [1, where R² is halogen, with the appropriate acid of formula ##STR18## (or alkali metal or tri-lower alkyl amine salt thereof) or with the appropriate alcohol of formula HOR¹³ (or alkali metal salt thereof), respectively. The reaction is run in excess acid or alcohol, respectively, or, optionally, in an inert organic solvent such as ethers such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane and the like; N,N-dialkylformamides, N,N-dialkylalkanoyl amides wherein alkyl and alkanoyl radicals have 1-4 carbons, such as dimethyl formamide, dimethylacetamide and the like. The reaction is carried out for from about 1/4 to about 72 hours, preferably about 1/2 to about 12 hours, at from about -20° C to about 150° C, preferably about 20° C to about 100° C. The products are isolated by conventional techniques as described in the first method.

The compounds of formula 1 where R² ═OH are obtained by reacting compounds of formula 1 where R² is ##STR19## with from about 0.2 to about 6, preferably about 0.8 to about 3, molar equivalents of an alkali metal (preferably sodium and potassium) hydroxide, bicarbonate or carbonate in an inert organic solvent, in optional presence of water. Suitable organic solvents include lower molecular weight alcohols, such as methanol, ethanol and the like; water-miscible ethers such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; N,N-dialkylformamides, N,N-dialkyl alkanoylamides wherein the alkyl and alkanoyl radicals have 1-4 carbons such as dimethylformamide, dimethylacetamide, and the like. The reaction is carried out at from about -50° C to about 100° C, preferably about -20° C to about 70° C, for from about 1/4 to about 72 hours, preferably about 1/2 to about 24 hours. The products are isolated in a conventional manner. For example, the reaction mixture is neutralized with acetic acid, evaporated and chromatographed.

The compounds of formula 1 where R² is halogen (preferably bromine or chlorine) are prepared by reacting compounds of formula 1 where R² with from about 0.5 to about 3, preferably from about 0.8 to about 1.3, molar equivalents of a lower alkyl N-haloamide, lower cycloalkyl N-haloimide or aryl sulfonyl N-haloamide, in the presence of a free radical catalyst, in an inert organic solvent. Suitable N-halo amides and imides include N-chloro and N-bromo-succinimide, and the like; N-chloroacetamide and the like; and N-chlorobenzenesulfonamide and the like. Suitable free radical catalysts include azobis-lower alkyl nitriles such as the preferred catalyst, azebisisobutyronitrile; di-lower alkyl peroxides such as di-t-butylperoxide; di-acyl peroxides such as acetyl peroxide; per esters such as t-butylperbenzoate; hydroperoxides such as t-butyl-hydroperoxide and the like. Typical inert organic solvents are aromatic hydrocarbons, such as benzene, toluene, xylene and the like; and chlorinated hydrocarbons such as methylene chloride, chlorobenzene, carbon tetrachloride, di-, tri- and tetrachloroethanes, chlorobenzene, and the like. The reaction is carried out at from about 25° C to about 200° C, preferably at about the reflux temperature of the reaction medium, for from about 1/4 to about 24 hours, preferably for from about 1/2 to about 5 hours. The product is isolated by conventional techniques. For example, the reaction mixture cooled to room temperature and evaporated.

Compounds of formula 1 where R² is alkyl of 1-4 carbons substituted by amino are prepared by reacting compounds of formula 1 where R² is hydrogen with from about 0.5 to about 12, preferably from about 0.8 to about 3.0 molar equivalents of an appropriate base, followed by reaction of the thus formed salt with a corresponding molar equivalent of an appropriate amino alkyl alkylating agent of formula R⁶ -M where R⁶ is the amino alkyl moiety and M is halogen, preferably chlorine, bromine, iodine; ##STR20## or an alkyl or arylsulfonate of formula ##STR21## where R⁷ can be alkyl of 1-6 carbons or aryl of from about 6 to 10 carbons optionally substituted by halogen, nitro or alkyl of 1-3 carbons, or R⁶ -M may be any other agent (within the definition of R⁶) capable of introducing an aminoalkyl group. The reaction is run in an essentially inert organic solvent.

Typical bases include alkali metal (preferably sodium and potassium) salts as well as thallous salts of lower molecular weight alkanols of 1-6 carbons such as methanol, ethanol, propanol, isopropal, t-butanol, amyl alcohol and the like; alkali metal (preferably sodium) hydrides; alkali metals (preferably sodium and potassium); alkali metal (preferably sodium and potassium) salts of acidic hydrocarbons such as triphenylmethane and the like as well as any other base known to those skilled in the art for generating salts of acidic methylene groups. Typical organic solvents include those described in the first method.

The reaction is carried out at from about -20° C to about 300° C, preferably from about 0° C to about 100° C for from about 0.2 hours to about 96 hours, preferably from about 0.5 hour to about 72 hours.

The products of formula 1 where R² is alkylamino are isolated by conventional techniques. For example the reaction mixture is evaporated; the residue is diluted with a water-immiscible, inert solvent such as methylene chloride, washed with water, dried and chromatographed.

Compounds of formula 1 can also be prepared by reacting compounds of formula 10 with at least from about 0.5 to a large excess, preferably at least from about 0.8 to about 100, molar equivalents of an aryl halide, in the presence of a copper catalyst, in an appropriate solvent containing from about 0.5 to about 1000, preferably about 0.8 to about 100, molar equivalents of an appropriate hydrogen halide acceptor. The preferred aryl halides are those of formula AR-K where AR is phenyl optionally substituted by X and where K is preferably chlorine, bromine or iodine. The preferred copper catalysts are powdered copper metal, copper oxides and cuprous and cupric salts. Typical solvents include N,N-dialkylformamides and N,N-dialkyl alkanoyl amides wherein the alkyl and alkanoyl radicals have 1-4 carbons such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; dialkyl sulfoxides of 2-6 carbons such as dimethyl sulfoxide and the like; and alkylphosphorous triamides of 4-10 carbons such as hexamethylphosphorous triamide. Appropriate hydrogen halide acceptors include alkali metal (preferably sodium or potassium) carbonates, bicarbonates, or lower alkyl carboxylic acid salts thereof (e.g., acetates). The reaction is carried out at from about 50° C to about 200° C, preferably at from about 90° C to about 180° C, for from about 1/4 to about 72 hours, preferably for from about 1/2 to about 14 hours. The product is isolated in a conventional manner. For example, the reaction mixture is diluted with methylene chloride, washed with dilute aqueous ammonium hydroxide and chromatographed.

Compounds of formula 2 where m is one are prepared by reacting compounds of formula 17 where m is one with from about 0.5 to about 10, preferably about 0.8 to about 2, molar equivalents of a malonyl dihalide (preferably malonyl dichloride or malonyl dibromide) or an alkyl malonic acid derivative (of formula ##STR22## in an inert organic solvent. Typical solvents are aromatic hydrocarbons such as benzene, toluene, xylene and the like; certain ethers such as dioxane, 1,2-dimethoxyethane, tetrahydrofuran and the like; chlorinated hydrocarbons such as di-, tri- and tetra-chloroethanes, chloroform, chlorobenzene, CCl₄, dichloroethane and the like; N,N-dialkylformamides and N,N-dialkyl alkanoylamides wherein the alkyl and alkanoyl radicals have 1-4 carbons such as N,N-dimethylformamide, N,N-dimethylacetamide and the like.

The reaction is carried out at from about -10° C to about 200° C, preferably at from about +10° C to about 140° C, for from about 1/4 to about 92 hours, preferably for from about 1 to about 24 hours. The products are isolated in a conventional manner. For example, the solvent is partially evaporated and the product filtered off.

Compounds of formula 2 where m is one are also prepared by reacting compounds of formula 17 where m is one with from about 0.5 to about 3, preferably from about 0.8 to about 1.4, molar equivalents of a malonic acid of the formula ##STR23## in an aqueous mineral acid. Typical mineral acids include sulfuric, hydrobromic and hydrochloric acid. The concentration of acid is from about 2 to about 7 normal, preferably from about 3.5 to about 4.5, normal. The reaction is carried out for from about 1/4 to about 92 hours, preferably for from about 1/2 to about 24 hours at from about 40° C to about 200° C, preferably from about 60° C to about 140° C. The product is isolated in a conventional manner. For example, the reaction is cooled and the product filtered off.

Compounds of formula 2 where m is one are also prepared by reacting compounds of formula 13 where m is one in the optional presence of a catalyst in the optional presence of water in an organic solvent. Typical catalysts include inorganic acids such as hydrogen chloride, hydrogen bromide and sulfuric acid as well as bases such as alkali metal (preferably sodium and potassium) hydroxides and lower alkoxides and other conventional bases used for the condensation of an aryl amine with an alkyl carboxylic acid ester. Typical solvents include alkanols of 1-6 carbons such as methanol, ethanol and the like; certain water-miscible ethers such as tetrahydrofuran, dioxane and the like; N,N-dialkylformamides and N,N-dialkyl alkanoyl amides wherein the alkyl and alkanoyl radicals have 1-4 carbons such as N,N-dimethyl formamide, dimethylacetamide and the like. The reaction is carried out for from about 1/2 to about 96 hours, preferably for from about 1 to about 24 hours at from about -20° C to about 150° C, preferably 0° C to 100° C. The product is isolated in a conventional manner. For example the reaction is neutralized, diluted with a water-immiscible inert organic solvent, washed with water, dried and chromatographed.

Compounds of formula 2 where m is one are also prepared by reacting compounds of formula 14 where m is one with an appropriate reducing agent, in the presence of an acid or base catalyst, in the optional presence of water in an organic solvent. Typical reducing systems include powdered iron, zinc and tin in the presence of an aqueous acid, in an optional organic solvent. Typical acids include hydrohalic acids (preferably hydrochloric acid) and alkyl carboxylic acids of 1- 6 carbon atoms such as acetic acid and the like. Typical solvent systems include aqueous alkanols of 1- 6 carbons such as methanol, ethanol and the like. Still other reducing agents include stannous chloride and aqueous hydrochloric acid; sodium hydrosulfite; ferrous sulfate and ammonium hydroxide; ammonium sulfide; hydrazine in the presence of palladized charcoal; sodium sulfide and ammonium chloride, sodium sulfide and sulfur. The reaction is carried out at from about 0° C to about 200° C, preferably at from about 10° C to about 140° C for from about 1/6 to about 92 hours, preferably for from about 1/2 to about 24 hours. The products are isolated by conventional techniques. For example the reaction is filtered, evaporated, saponified in alcoholic potassium hydroxide, evaporated, taken up in water, adjusted to pH 6 and the product filtered off and chromatographed.

Compounds of formula 2, where m is zero are prepared from compounds of formulas 13, 14 and 17 where m is zero by the methods described for the preparation of compounds of formula 2, where m is one [see also: Chemical Reviews, 68, 780ff( 1968) and references cited therein and, S. African patent 6800803 (1968)].

Compounds of formula 3 can be prepared by reacting compounds of formula 2 with from about 0.5 to about 2.0, preferably with from about 0.9 to about 1.2, molar equivalents of phosphorous pentasulfide in an aprotic, essentially inert organic solvent. Typical inert organic solvents include aryl hydrocarbons such as benzene, toluene or xylene; aliphatic hydrocarbons of 5-12 carbons, such as hexane, heptane and the like; alicyclic hydrocarbons of 5-8 carbons, such as cyclohexane and the like; basic carbocyclic amines such as pyridine, quinoline, γ-picoline and the like; and any other conventional solvent materials which are relatively inert with regard to the starting materials.

The reaction is carried out at from about 10° C to about 250° C, preferably at from about 50° C to about 150° C, for from about 5 minutes to about 72 hours, preferably from about 10 minutes to about 6hours. The product of formula 3 is isolated by conventional techniques. For example the reaction solvent is evaporated, the residue stirred with ice water, extracted into a water-immiscible organic solvent; the water-immiscible solvent is washed consecutively with water, dilute aqueous hydrohalic acid, dried and chromatographed.

Compounds of formula 4 are prepared by reacting compounds of formula 3 with from about 0.5 to about 6, preferably from about 0.8 to about 1.2, molar equivalents of an alkylating agent of formula R³ -M [where M may be halogen, preferably bromine or iodine ##STR24## or an alkyl or arylsulfonate moiety of formula ##STR25## where R⁷ can be alkyl of 1-6 carbons or aryl of from 6 to 10 carbons optionally substituted by halogen, nitro or alkyl of 1-3 carbons or R³ -M may be any other agent (within the definition of R³) capable of selectively alkylating the sulfur atom in the presence of the other groups in 3] in the presence of an appropriate base in an inert organic solvent. Typical bases include alkali metal hydroxides (preferably sodium and potassium hydroxide), alkali metal carbonates (preferably sodium and potassium bicarbonate or carbonate) and appropriate organic tertiary amines such as trialkylamines, e.g., triethylamine and the like, and pyridine and the like. Typical solvents include lower molecular weight alkanols of 1-6 carbons such as methanol, ethanol and the like; water-miscible ethers such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane and the like; N,N-dialkylformamides and N,N-dialkyl alkanoyl amides wherein the alkyl and alkanoyl radicals have 1-4 carbon atoms such as dimethyl formamide or dimethylacetamide and the like; alkyl ketones of 2-5 carbons such as acetone, methylethylketone and the like, and dimethyl sulfoxide. The reaction is carried out at from about -60° C to about 150° C, preferably at from about 0° C to about 90° C, for from about 1 minute to about 90 hours, preferably for from about 5 minutes to about 24 hours. The products of formula 4 are isolated by conventional techniques. For example, the reaction is diluted with water, extracted with a water-immiscible solvent, dried and chromatographed.

Compounds of formula 5 can be prepared by reacting compounds of formula 2 with from about 0.5 to about 3, preferably with from about 0.8 to about 1.2, molar equivalents of a suitable halogenating agent in an inert organic solvent, in the optional presence of an acid proton acceptor. Typical halogenating agents include the phosphorous halides such as phosphorous pentachloride, phosphorous oxychloride, and phosphorous oxybromide. Typical inert organic solvents include aromatic hydrocarbons such as benzene, toluene xylene and the like; chlorinated hydrocarbons such as methylene chloride, chloroform, chlorobenzene, CC1₄, di-, tri- and tetrachloroethanes and the like. Phosphorous oxyhalides such as phosphorous oxychloride and the like can be used both as solvent and halogenating agent.

Optional acid proton acceptors include N,N-di-lower alkyl aryl amines such as N,N-dimethylaniline, N,N-diethylaniline and the like and trialkylamines such as triethylamine, tributylamine and the like.

The reaction is carried out at from about 0° C to about 200° C, preferably at from about 40° C to about 150° C, for from about 1/4 to about 72 hours, preferably for from 178 to about 24 hours. The products of formula 5 are isolated by conventional techniques. For example, the reaction mixture is evaporated and the residue is diluted with an aprotic, inert, organic solvent, washed with cold water, and then evaporated. The residual product is stirred with a non-solubilizing inert organic solvent, such as carbon tetrachloride, and the product is filtered off.

Compounds of formula 6 are prepared by reacting compounds of formula 2 with from about 0.8 to about 50, preferably about 1 to about 20, molar equivalents of a diazo-lower alkane in an inert organic solvent. Typical inert organic solvents include lower molecular weight ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; alkanols of 1-6 carbons such as methanol, ethanol and the like and halogenated hydrocarbons such as chloroform methylene chloride, CC1₄, 1,2-dichloroethane, chlorobenzene, di-, tri- and tetrachloroethanes and the like.

The reaction is carried out at from about -50° C to about 100° C, preferably at from about 0° C to about 60° C for from about 1/4 hour to about 72 hours preferably for from about 1/2 to about 12 hours.

The products of formula 6 are isolated by conventional techniques. For example, the reaction is filtered, evaporated and chromatographed.

Another method for the preparation of compounds of formula 6 involves reacting compounds of formula 2 with from about 0.5 to about 3, preferably with from about 0.8 to about 1.4, molar equivalents of a tri-lower alkyl oxonium fluoroborate in an inert organic solvent. Typical solvents include halogenated hydrocarbons such as methylene chloride, CC1₄, chloroform, 1,2-dichloroethane, chlorobenzene, di-, tri- and tetrachloroethanes and the like. The reaction is carried out at from about -50° C to about 100° C, preferably at from about -20° C to about 70° C for from about 178 hour to about 72 hours preferably for from about 1 to about 24 hours.

The products of formula 6 are isolated by conventional techniques. For example, the reaction mixture is washed with cold aqueous potassium bicarbonate, dried and the solvent evaporated.

Compounds of formula 7 are prepared by reacting compounds of formulas 3-6 with from about 0.8 to about 6.0, preferably with from about 1 to about 3, molar equivalents of an acid hydrazide of formula ##STR26## in an inert organic solvent. Typical solvents include alkanols of 1-6 carbons such as methanol, ethanol, t-butanol, n-butanol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; chlorinated hydrocarbons such as methylene chloride, chloroform, di-, tri- and tetrachloroethane and the like; ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; N,N-dialkylformamides, N,N-dialkyl alkanoyl amides wherein the alkyl and alkanoyl radicals have from 1-4 carbons, such as N,N-dimethyl formamide, N,N-dimethylacetamide and the like; hexamethylenephosphorous triamide and dimethyl sulfoxide. The reaction is carried out at from about -30° C to about 160° C preferably at from about 30° C to about 120° C, for from about 1/2 to about 96 hours, preferably for from about 2 to about 12 hours. The products of formula 7 are isolated by conventional techniques. For example, the reaction is diluted with a water-immiscible inert organic solvent, washed with water, dried and chromatographed.

Compounds of formula B are prepared by reacting compounds of formula 9 with at least about 0.1 preferably from about 0.8 to about 3, molar equivalents of an inorganic hydrohalic acid, preferably hydrogen bromide or hydrogen chloride in an inert organic solvent. Typical inert organic solvents include alkanols of 1-6 carbons such as ethanol, t-butanol and the like; lower molecular weight ethers such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane and the like; chlorinated hydrocarbons such as methylene chloride, CC1₄, chlorobenzene, di-, tri-, and tetrachloroethanes, chloroform and the like; N,N-dialkylformamides, N,N-dialkyl alkanoyl amides wherein the alkyl and alkanoyl radicals have 1-4 carbons, such as dimethyl formamide, dimethylacetamide and the like. The reaction is run for from about 174 to about 90 hours, preferably for from about 178 to about 3 hours, at from about -50° C to about 100° C, preferably at from about -30° to about 80° C. For example, the solvent is evaporated at room temperature in vacuo, the residue stirred in cold water containing an alkali metal hydroxide, equivalent in molar amount to the amount of hydrohalic acid used, and the product is then removed by filtration and dried.

Compounds of formula 9 are prepared by reacting compounds of formulas 3-6 with from about 0.5 to about 6, preferably with from about 0.8 to about 3, molar equivalents of a compound of formula ##STR27## in an inert organic solvent. Typical solvents are those as defined in the first method. The reaction is carried out at from about 40° C to about 250° C, preferably at from about 50° C to about 180° C for from about 1/4 hours to about 92 hours, preferably about 1 to about 48 hours. The products of formula 9 are isolated by conventional techniques as described in the first method.

Compounds of formula 10 are prepared by the removal of the N⁶ benzyl group in compounds of formula 11 wherein the benzyl group is replaced by hydrogen. Suitable reagents and conditions are those described below for the debenzylation of compounds of formula 12. The isolation of the products is as exemplified for compounds of formula 12.

Compounds of formula 12 are prepared by reacting compounds of formulas 3-6 wherein m is zero with from about 0.5 to about 6, preferably with from about 0.8 to about 3, molar equivalents of an acid hydrazide of formula ##STR28## in an inert organic solvent. Typical solvents, the conditions of the reaction and the isolation of the product are as described in the first method.

Compounds of formula 13 are prepared by reacting compounds of formula 14 with an appropriate reducing agent under selective conditions in an inert organic solvent.

Typical reducing agents include a metal catalyst, preferably Raney nickel, and hydrogen in the optional presence of a hydrogen halide in an inert organic solvent. Typical solvents include alkanols of 1-6 carbons such as methanol, ethanol and the like. The preferred optional hydrogen halides are hydrogen chloride and hydrogen bromide. The reactions are carried out for from about 1/6 hour to about 92 hours, preferably for from about 178 to about 24 hours at from about 0° C to about 150° C, preferably at from about 10° C to about 120° C. Hydrogen pressures are from about 0.1 to about 100 atm. preferably about 0.8 to about 10 atm. The reaction is stopped after approximately three molar equivalents of hydrogen have been absorbed. The products are isolated in a conventional manner. For example the reaction is filtered, made alkaline to pH 8, extracted with a water-miscible organic solvent, washed with water, dried and chromatographed.

Compounds of formula 14 are prepared by reacting compounds of formula 15 with from about 0.5 to about 6, preferably with from about 0.8 to about 2, molar equivalents of a compound of formula 16 (where B is halogen, preferably chlorine or bromine, or a group of formula ##STR29## in an inert organic solvent. Typical solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as chloroform, methylene chloride, CC1₄, chlorobenzene, di-, tri- and tetrachloroethane and the like; certain ethers such as 1,2-dimethoxyethane, dioxane, tetrahydrofuran and the like; N,N-dialkylformamides, N,N-dialkyl alkanoyl amides wherein the alkyl and alkanoyl radicals have 1-4 carbons, such as N,N-dimethyl amide and the like. The reactions are carried out for from about 178 to about 92 hours, preferably for from about 2 to about 24 hours at from about -20° C to about 150° C, preferably at from about +5° C to about 100° C. The products are isolated by conventional techniques as exemplified in the first method.

Compounds of formula 17 are prepared by reacting compounds of formula 15 with an appropriate reducing agent in an essentially inert organic solvent. Typical reducing agents include a metal catalyst such as palladium, platinum and the preferred catalyst Raney nickel in the presence of hydrogen in the optional presence of a hydrogen halide (preferably hydrogen chloride and hydrogen bromide). Typical solvents include alkanols of 1 to 6 carbons such as methanol, ethanol, propanol, isopropanol and the like.

Hydrogen pressures are from about 0.1 to about 100 atm., preferably from about 0.8 to about 10 atm. The reaction is stopped after approximately three molar equivalents of hydrogen have been absorbed.

The reaction is carried out at from about 0° C to to about 150° C, preferably from about 20° C to about 100° C for from about 0.2 to about 96 hours, preferably from about 0.5 hour to about 24 hours.

The products of formula 17 are isolated by conventional techniques. For example the reaction is filtered, made alkaline to pH 8, diluted with a water-immiscible, inert organic solvent, washed with water, dried and evaporated.

Compounds of formula 15 are prepared by reacting compounds of formula 18 with at least about 0.2 molar equivalents, preferably from about 0.8 to about 100 molar equivalents of a compound of formula 19 in the optional presence of a hydrogen halide acceptor in the optional presence of an inert organic solvent.

Typical hydrogen halide acceptors include alkali metal (preferably sodium or potassium) carbonates, bicarbonates, or lower alkyl carboxylic acid salts thereof (e.g., acetates).

Typical solvents include nitrohydrocarbons such as nitrobenzene and the like; lower alkanols of 1-6 carbons such as ethanol, t-butanol, butanol and the like.

The reaction is carried out at from about 25° C to about 300° C, preferably from about 50° C to about 250° C for from about 0.2 hour to about 96 hours, preferably from about 1 hour to about 48 hours.

The products of formula 15 are isolated by conventional techniques. For example the reaction is poured into excess dilute hydrochloric acid and extracted with ether. For products of formula 15 where m is zero, the ether is dried, evaporated and the residual crude product is chromatographed.

For products of formula 15 where m is one, the above obtained aqueous hydrochloric acid extract is made alkaline to pH 9 and extracted with ether. The ether is dried, evaporated and the residual product is chromatographed.

For compounds of formula 15 where m is zero see also Chemical Abstracts, 43, 6175d (1948).

For compounds of formula 15 where m is one see also Proc. Indian Acad. Sci., 47A, 77 (1958).

For compounds of formula 16 see Acta Chem. Scand., 15,260 (1961).

The novel compounds of formula I are CNS depressants and are useful as, for example, sedatives, tranquilizers, hypnotics, anticonvulsants and muscle relaxants in mammalian species, e.g. rats, mice and monkeys. They are also useful as feed additives for increasing growth rate and feed efficiency in mammalian species, such as livestock, specifically swine and cattle. The CNS depressant effects of compounds of this invention are shown, for example, by the following tests in animals. Thus, for example, oral administration of a compound of the invention produces ataxia at dosage levels of from about 0.1 to about 10 mg/kg, specifically, in rats at about 3.1 mg/kg, in mice at about 1 mg/kg and in monkeys at about 2.5 mg/kg.

The compounds of the present invention produce a significant tranquilizing effect at a dosage level of from about 0.1 to about 25 mg/kg, specifically at a dosage level of about 6.2 mg/kg when administered via the oral route to rats in a conflict test procedure [cf. J. R. Vogel, B. Beer, D. Clody, Psychopharmacologist, 21, 1 (1970)].

In mice, oral administration of from about 0.1 to about 50 mg/kg of a compound of the present invention antagonizes the convulsant effects of subcutaneously administered pentylenetetrazole and of intraveneously administered strychnine.

Mice treated with from about 0.01 to about 200 mg/kg of a compound of the present invention via the oral route increase significantly their food consumption.

The compounds of the present invention in the described dosages may be administered orally; however, other routes such as intraperitoneally, subcutaneously, intramuscularly or intravenously may be employed.

The active compounds of the present invention are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 5% to about 75% or more of the weight of the unit. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 10 and 500 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.

In the following examples all reactions are run under an inert atmosphere (e.g. argon), at room temperature, using anhydrous solvents unless otherwise indicated; in addition, reactions which are heated are subsequently cooled to room temperature for work-up. In general, solvents are evaporated in a rotary flash vacuum apparatus. In this patent application, the full name of the parent ring system of compounds described as indicated in Column I below is as indicated in Column II.

    ______________________________________                                         I                      II                                                      ______________________________________                                         "4H-s-triazolo[4,3-a][1,5]-                                                                        "5,6-dihydro-4H-s-                                         benzodiazepin"      triazolo[4,3-a][1,5]-                                                          benzodiazepin"                                             "1H-1,5-benzodiazepin"                                                                             "2,3,4,5-tetrahydro-1H-                                                        1,5-benzodiazepin"                                         "3H-1,5-benzodiazepin"                                                                             "4,5-dihydro-3H-1,5-                                                           benzodiazepin"                                             ______________________________________                                    

EXAMPLE 1 7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione

A solution of 28.6 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione and 23.3 g of phosphorous pentasulfide in 250 ml of pyridine is refluxed, with stirring, for 40 minutes under argon. The solvent is evaporated in vacuo.

The residue is stirred in ice water and extracted with methylene chloride. The organic phase is washed consecutively with dilute aqueous hydrochloric acid, water and dried. The organic phase is filtered through a short column of neutral III alumina, the column is washed with ethyl acetate and the filtrate evaporated. The residue is triturated with a small amount of hot benzene and the product filtered off and dried.

EXAMPLES 2 - 28

Following the procedure of Example 1 but substituting the compounds indicated in Column I below for 7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione in Example 1, the compounds indicated in Column II are obtained:

    ______________________________________                                            I                  II                                                       ______________________________________                                         2.    5-phenyl-1H-1,5-benzo-                                                                           5-phenyl-1H-1,5-benzo-                                       diazepine-2,4-dione                                                                              diazepin-4-one-2-thione                                3.    7-(trifluoromethyl)-5-                                                                           7-(trifluoromethyl)-5-                                       phenyl-1H-1,5-benzodia-                                                                          phenyl-1H-1,5-benzodia-                                      zepine-2,4-dione  zepin-4-one-2-thione                                   4.    7-nitro-5-phenyl-1H-1,5-                                                                         7-nitro-5-phenyl-1H-                                         benzodiazepine-2,4-dione                                                                         1,5-benzodiazepin-4-                                                           one-2-thione                                           5.    7-methyl-5-phenyl-1H-                                                                            7-methyl-5-phenyl-1H-                                        1,5-benzodiazepine-                                                                              1,5-benzodiazepin-4-                                         2,4-dione         one-2-thione                                           6.    7-methoxy-5-phenyl-                                                                              7-methoxy-5-phenyl-1H-                                       1H-1,5-benzodia-  1,5-benzodiazepin-4-                                         zepine-2,4-dione  one-2-thione                                           7.    7-(methylthio)-5- 7-(methylthio)-5-                                            phenyl-1H-1,5-benzo-                                                                             phenyl-1H-1,5-benzo-                                         diazepine-2,4-dione                                                                              diazepin-4-one-2-thione                                8.    7-pentyl-5-phenyl-1H-                                                                            7-pentyl-5-phenyl-1H-                                        1,5-benzodiazepine-                                                                              1,5-benzodiazepin-4-                                         2,4-dione         one-2-thione                                           9.    7-pentoxy-5-phenyl-                                                                              7-pentoxy-5-phenyl-1H-                                       1H-1,5-benzodiazepine-                                                                           1,5-benzodiazepin-4-                                         2,4-dione         one-2-thione                                           10.   7-bromo-5-phenyl-1H-                                                                             7-bromo-5-phenyl-1H-                                         1,5-benzodiazepine-                                                                              1,5-benzodiazepin-4-                                         2,4-dione         one-2-thione                                           11.   7-fluoro-5-phenyl-1H-                                                                            7-fluoro-5-phenyl-1H-                                        1,5-benzodiazepine-                                                                              1,5-benzodiazepin-4-                                         2,4-dione         one-2-thione                                           12.   7-cyano-5-phenyl-1H-                                                                             7-cyano-5-phenyl-1H-                                         1,5-benzodiazepine-                                                                              1,5-benzodiazepin-4-                                         2,4-dione         one-2-thione                                           13.   7-chloro-5-(2-chloro-                                                                            7-chloro-5-(2-chloro-                                        phenyl)-1H-1,5-benzo-                                                                            phenyl)-1H-1,5-benzodia-                                     diazepine-2,4-dione                                                                              zepin-4-one-2-thione                                   14.   7-chloro-5-(2-fluoro-                                                                            7-chloro-5-(2-fluoro-                                        phenyl)-1H-1,5-benzo-                                                                            phenyl)-1H-1,5-benzo-                                        diazepine-2,4-dione                                                                              diazepin-4-one-2-thione                                15.   7-chloro-5-(3-chloro-                                                                            7-chloro-5-(3-chloro-                                        phenyl)-1H-1,5-benzo-                                                                            phenyl)1H,1,5-benzodia-                                      diazepine-2,4-dione                                                                              zepin-4-one-2-thione                                   16.   7-chloro-5-(4-chloro-                                                                            7-chloro-5-(4-chloro-                                        phenyl)-1H-1,5-benzo-                                                                            phenyl)-1H-1,5-benzo-                                        diazepine-2,4-dione                                                                              diazepin-4-one-2-thione                                17.   7-chloro-5-(2-methoxy-                                                                           7-chloro-5-(2-methoxy-                                       phenyl)-1H-1,5-benzo-                                                                            phenyl)-1H-1,5-benzo-                                        diazepine-2,4-dione                                                                              diazepin-4-one-2-thione                                18.   7-chloro-5-(3-methoxy-                                                                           7-chloro-5-(3-methoxy-                                       phenyl)-1H-1,5-benzo-                                                                            phenyl)-1H-1,5-benzo-                                        diazepine-2,4-dione                                                                              diazepin-4-one-2-thione                                19.   7-chloro-5-(4-methoxy-                                                                           7-chloro-5-(4-methoxy-                                       phenyl)-1H-1,5-benzo-                                                                            phenyl)-1H-1,5-benzo-                                        diazepine-2,4-dione                                                                              diazepin-4-one-2-thione                                20.   7-chloro-5-(2-methyl-                                                                            7-chloro-5-(2-methyl-                                        phenyl)-1H-1,5-benzo-                                                                            phenyl)-1H-1,5-benzo-                                        diazepine-2,4-dione                                                                              diazepin-4-one-2-thione                                21.   7-chloro-5-(3-methyl-                                                                            7-chloro-5-(3-methyl-                                        phenyl)-1H-1,5-benzo-                                                                            phenyl)-1H-1,5-benzo-                                        diazepine-2,4-dione                                                                              diazepin-4-one-2-thione                                22.   7-chloro-5-(4-methyl-                                                                            7-chloro-5-(4-methyl-                                        phenyl)1H-1,5-benzo-                                                                             phenyl)-1H-1,5-benzo-                                        diazepine-2,4-dione                                                                              diazepin-4-one-2-thione                                23.   3-methyl-7-chloro-5-                                                                             3-methyl-7-chloro-5-                                         phenyl-1H-1,5-benzodia-                                                                          phenyl-1H-1,5-benzodia-                                      zepine-2,4-dione  zepin-4-one-2-thione                                   24.   3-(benzyloxy)-7-chloro-                                                                          3-(benzyloxy)-7-chloro-                                      5-phenyl-1H-1,5-benzo-                                                                           5-phenyl-1H-1,5-benzo-                                       diazepine-2,4-dione                                                                              diazepin-4-one-2-thione                                25.   3-methoxy-7-chloro-5-                                                                            3-methoxy-7-chloro-5-                                        phenyl-1H-1,5-benzo-                                                                             phenyl-1H-1,5-benzo-                                         diazepine-2,4-dione                                                                              diazepin-4-one-2-thione                                26.   8-methyl-5-phenyl-1H-                                                                            8-methyl-5-phenyl-1H-                                        1,5-benzodiazepine-                                                                              1,5-benzodiazepin-4-                                         2,4-dione         one-2-thione                                           27.   8-chloro-5-phenyl-                                                                               8-chloro-5-phenyl-1H-                                        1H-1,5-benzodiazepine-                                                                           1,5-benzodiazepin-4-                                         2,4-dione         one-2-thione                                           28.   8-(trifluoromethyl)-5-                                                                           8-(trifluoromethyl)-5-                                       phenyl-1H-1,5-benzodia-                                                                          phenyl-1H-1,5-benzodia-                                      zepine-2,4-dione  zepin-4-one-2-thione                                   ______________________________________                                    

EXAMPLE 29 1-Methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]-benzodiazepin-5-one Method A

30.2 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione and 23.8 g of acetic acid hydrazide in a mixture of 640 ml n-butanol and 160 ml of dimethyl sulfoxide are refluxed with stirring for 24 hours. During this time, argon is bubbled through the reaction mixture. The reaction is concentrated in vacuo and partitioned between methylene chloride and water; the organic phase is washed several times with water, dried and filtered through a short Florisil column. After eluting the column with ethyl acetate, the combined filtrates are evaporated to give the title compound. Recrystallization from ethanol-ethyl acetate, followed by vacuum drying at elevated temperatures gives the product.

Method B

15.8 g of 2-(methylthio)-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one and 8.1 g of acetic acid hydrazide in 400 ml dimethyl formamide are refluxed with stirring for 24 hours. During this time nitrogen is bubbled through the reaction mixture. The reaction mixture is worked up as described in Example 29, Method A, to give the title compound.

Method C

A mixture of 6.2 g of 1-methyl-8-chloro-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one, 5 g of copper powder and 2.5 g of potassium acetate in 100 ml bromobenzene are refluxed for six hours with stirring. The reaction is diluted with methylene chloride, filtered through a short Florisil column and the filtrate washed with dilute aqueous ammonium hydroxide. The organic phase is washed with water, dried and the solvent evaporated to give the title compound.

Method D

3.0 g of 2,7-dichloro-5-phenyl-3H-1,5-benzodiazepin-4-one and 1.8 g of acetic acid hydrazide in 50 ml of dioxane are refluxed under argon for 24 hours. 2 ml of water is then added, the reaction stirred for 1 hour and the solvent evaporated. The residue is taken up in methylene chloride, washed with dilute aqueous sodium bicarbonate, with water and dried. The solvent is evaporated and the residue is chromatographed on ten-1000μ silica gel thick layer plates (20 × 20 cm) with ethyl acetate-ethanol (9:1) as eluant. The main band, having an approximate Rf range of 0.12-0.28, is removed, stirred with acetone-methanol (9:1) and the silica gel filtered off. The filtrate is evaporated to give the title compound.

Method E

Following the procedure of Example 29, Method B, but substituting 15 g of 2-methoxy-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one for 15.8 g of 2-(methylthio)-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one in Example 29, Method B, the title compound is obtained.

Method F

15 g of acetic acid 2-(7-chloro-5-phenyl-3H-1,5 -benzodiazepin-4-one-2-yl)hydrazide in 100 ml dimethyl formamide are refluxed for 24 hours under a Soxhlet extractor containing 4A molecular sieves, under argon. The solvent is evaporated and the crude product is purified as described in Example 29, Method D.

Method G

3.01 g of 2-hydrazino-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one in 15 ml of acetic anhydride is refluxed for 24 hours. The acetic anhydride is evaporated and the residual crude product taken up in methylene chloride and purified as described in Example 29, Method D.

Method H

4.0 g of 2-[2-(t-butoxycarbonyl)hydrazino]-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one in 60 ml of n-butyl acetate which contains 2.0 g of hydrogen bromide is stirred at room temperature for 1 hour and refluxed for 24 hours. The reaction is evaporated, the product dissolved in methylene chloride and purified as described in Example 29, Method D.

Method I

To 4.96 g of 1-methyl-8-chloro-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in a mixture of 70 ml ethanol and 200 ml of 0.1 N aqueous potassium hydroxide is added 7.2 g of diphenyliodonium bromide. The reaction is refluxed for 8 hours. The iodobenzene is removed by steam distillation. The distillation residue is cooled and partitioned between methylene chloride and water. The organic phase is dried and evaporated to give the title compound.

EXAMPLES 30-55

Following the procedure of Example 29, Method A, but substituting the compounds indicated in Column I below for 7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione in Example 29, Method A, the compounds indicated in Column II are obtained.

    ______________________________________                                         I                      II                                                      ______________________________________                                         30.   5-phenyl-1H-1,5-benzo-                                                                           1-methyl-6-phenyl-4H-s-                                      diazepin-4-one-2-thione                                                                          triazolo[4,3-a][1,5]-                                                          benzodiazepin-5-one                                    31.   7-(trifluoro-methyl)-5-                                                                          1-methyl-8-(trifluoro-                                       phenyl-1H-1,5-benzodia-                                                                          methyl)-6-phenyl-4H-s-                                       zepin-4-one-2-thione                                                                             triazolo[4,3-a][1,5]-                                                          benzodiazepin-5-one                                    32.   7-nitro-5-phenyl-1H                                                                              1-methyl-8-nitro-6-                                          1,5-benzodiazepin-4-                                                                             phenyl-4H-s-triazolo-                                        one-2-thione      [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            33.   7-methyl-5-phenyl-                                                                               1-methyl-8-methyl-6-                                         1H-1,5-benzodiazepin-                                                                            phenyl-4H-s-triazolo-                                        4-one-2-thione    [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            34.   7-methoxy-5-phenyl-                                                                              1-methyl-8-methoxy-                                          1H-1,5-benzodiazepin-                                                                            6-phenyl-4H-s-triazolo-                                      4-one-2-thione    [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            35.   7-(methylthio)-5-phenyl-                                                                         1-methyl-8-(methyl-                                          1H-1,5-benzodiazepin-                                                                            thio)-6-phenyl-4H-                                           4-one-2-thione    s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                    36.   7-pentyl-5-phenyl-1H-                                                                            1-methyl-8-pentyl-6-                                         1,5-benzodiazepin-4-one-                                                                         phenyl-4H-s-triazolo-                                        2-thione          [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            37.   7-pentoxy-5-phenyl-1H-                                                                           1-methyl-8-pentoxy-6-                                        1,5-benzodiazepin-4-                                                                             phenyl-4H-s-triazolo-                                        one-2-thione      [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            38.   7-bromo-5-phenyl-1H-                                                                             1-methyl-8-bromo-6-                                          1,5-benzodiazepin-4-                                                                             phenyl-4H-s-triazolo-                                        one-2-thione      [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            39.   7-fluoro-5-phenyl-1H-                                                                            1-methyl-8-fluoro-6-                                         1,5-benzodiazepin-4-                                                                             phenyl-4H-s-triazolo-                                        one-2-thione      [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            40.   7-cyano-5-phenyl-1H-                                                                             1-methyl-8-cyano-6-                                          1,5-benzodiazepin-4-                                                                             phenyl-4H-s-triazolo-                                        one-2-thione      [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            41.   7-chloro-5-(2-chloro-                                                                            1-methyl-8-chloro-6-                                         phenyl)-1H-1,5-benzo-                                                                            (2-chlorophenyl)-4H-s-                                       diazepin-4-one-2-thione                                                                          triazolo[4,3-a][1,5]-                                                          benzodiazepin-5-one                                    42.   7-chloro-5-(2-fluoro-                                                                            1-methyl-8-chloro-6-                                         phenyl)-1H-1,5-benzo-                                                                            (2-fluorophenyl)-4H-                                         diazepin-4-one-2-thione                                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                    43.   7-chloro-5-(3-chloro-                                                                            1-methyl-8-chloro-6-                                         phenyl)-1H-1,5-benzo-                                                                            (3-chlorophenyl)-4H-                                         diazepin-4-one-2-thione                                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                    44.   7-chloro-5-(4-chloro-                                                                            1-methyl-8-chloro-6-                                         phenyl)-1H-1,5-benzo-                                                                            (4-chlorophenyl)-4H-s-                                       diazepin-4-one-2-thione                                                                          triazolo[4,3-a][1,5]-                                                          benzodiazepin-5-one                                    45.   7-chloro-5-(2-methoxy-                                                                           1-methyl-8-chloro-6-                                         phenyl)-1H-1,5-benzo-                                                                            (2-methoxyphenyl)-4H-                                        diazepin-4-one-2-thione                                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                    46.   7-chloro-5-(3-methoxy-                                                                           1-methyl-8-chloro-6-                                         phenyl)-1H-1,5-benzo-                                                                            (3-methoxyphenyl)-4H-                                        diazepin-4-one-2-thione                                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                    47.   7-chloro-5-(2-methyl-                                                                            1-methyl-8-chloro-6-                                         phenyl)-1H-1,5-benzo-                                                                            (2-methylphenyl)-4H-                                         diazepin-4-one-2-thione                                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                    48.   7-chloro-5-(3-methyl-                                                                            1-methyl-8-chloro-6-                                         phenyl)-1H-1,5-benzo-                                                                            (3-methylphenyl)-4H-                                         diazepin-4-one-2-thione                                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                    49.   7-chloro-5-(4-methyl-                                                                            1-methyl-8-chloro-6-                                         phenyl)-1H-1,5-benzo-                                                                            (4-methylphenyl)-4H-                                         diazepin-4-one-2-thione                                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                    50.   3-methyl-7-chloro-5-                                                                             1,4-dimethyl-8-chloro-                                       phenyl-1H-1,5-benzo-                                                                             6-phenyl-4H-s-triazolo-                                      diazepin-4-one-2-thione                                                                          [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            51.   3-(benzyloxy)-7-chloro-                                                                          4-(benzyloxy)-1-methyl-8-                                    5-phenyl-1H-1,5-benzodia-                                                                        chloro-6-phenyl-4H-s-                                        zepin-4-one-2-thione                                                                             triazolo[4,3-a][1,5]-                                                          benzodiazepin-5-one                                    52.   3-methoxy-7-chloro-5-                                                                            4-(methoxy)-1-methyl-8-                                      phenyl-1H-1,5-benzo-                                                                             chloro-6-phenyl-4H-s-                                        diazepin-4-one-2-thione                                                                          triazolo[4,3-a][1,5]-                                                          benzodiazepin-5-one                                    53.   8-methyl-5-phenyl-1H-                                                                            1,9-dimethyl-6-phenyl-                                       1,5-benzodiazepin-4-                                                                             4H-s-triazolo[4,3-a]-                                        one-2-thione      [1,5]benzodiazepin-5-                                                          one                                                    54.   8-chloro-5-phenyl-1H-                                                                            9-chloro-1-methyl-6-                                         1,5-benzodiazepin-4-                                                                             phenyl-4H-s-triazolo-                                        one-2-thione      [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            55.   8-(trifluoromethyl)-5-                                                                           9-(trifluoromethyl)-                                         phenyl-1H-1,5-benzo-                                                                             1-methyl-6-phenyl-4H-                                        diazepin-4-one-2- s-triazolo[4,3-a][1,5]-                                      thione            benzodiazepin-5-one                                    ______________________________________                                    

EXAMPLES 56 - 64

Following the procedure of Example 29, Method A, but substituting the acid hydrazides indicated in Column I below for acetic acid hydrazide in Example 29, Method A, the compounds indicated in Column II are obtained.

    ______________________________________                                                I               II                                                      ______________________________________                                         56.   formic acid hydrazide                                                                            8-chloro-6-phenyl-4H-s-                                                        triazolo[4,3-a][1,5]-                                                          benzodiazepin-5-one                                    57.   propionic acid hydrazide                                                                         1-ethyl-8-chloro-6-                                                            phenyl-4H-s-triazolo-                                                          [4,3-a][1,5]benzodiaze-                                                        pin-5-one                                              58.   valeric acid hydrazide                                                                           1-butyl-8-chloro-6-                                                            phenyl-4H-s-triazolo-                                                          [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            59.   cyclopropane carboxylic                                                                          1-cyclopropyl-8-chloro-                                      acid hydrazide    6-phenyl-4H-s-triazolo-                                                        [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            60.   cyclopentane carboxylic                                                                          1-cyclopentyl-8-chloro-                                      acid hydrazide    6-phenyl-4H-s-triazolo-                                                        [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            61.   phenylacetic acid 1-benzyl-8-chloro-                                           hydrazide         6-phenyl-4H-s-triazolo-                                                        [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            62.   2-methyl-propionic                                                                               1-isopropyl-8-chloro-                                        acid hydrazide    6-phenyl-4H-s-triazolo-                                                        [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            63.   1-cyanoacetic acid                                                                               1-cyanomethyl-8-chloro-                                      hydrazide         6-phenyl-4H-s-triazolo-                                                        [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            64.   benzoic acid hydrazide                                                                           1-phenyl-8-chloro-                                                             6-phenyl-4H-s-triazolo-                                                        [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            ______________________________________                                    

EXAMPLES 65 - 91

Following the procedure of Example 29, Method A, but substituting formic acid hydrazide for acetic acid hydrazide in Example 29, Method A, and the compounds indicated in Column I below for 7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione in Example 29, Method A, the compounds indicated in Column II are obtained.

    ______________________________________                                                I               II                                                      ______________________________________                                         65.   5-phenyl-1H-1,5-benzodia-                                                                        6-phenyl-4H-                                                 zepin-4-one-2-thione                                                                             s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                    66.   7-(trifluoromethyl-5-                                                                            8-(trifluoro-                                                phenyl-1H-1,5-benzodia-                                                                          methyl)-6-phenyl-4H-s-                                       zepin-4-one-2-thione                                                                             triazolo[4,3-a][1,5]-                                                          benzodiazepin-5-one                                    67.   7-nitro-5-phenyl-1H-                                                                             8-nitro-6-phenyl-4H-                                         1,5-benzodiazepin-4-                                                                             s-triazolo-[4,3-a][1,5]-                                     one-2-thione      benzodiazepin-5-one                                    68.   7-methyl-5-phenyl-1H-                                                                            8-methyl-6-phenyl-4H-                                        1,5-benzodiazepin-4-                                                                             s-triazolo[4,3-a][1,5]-                                      one-2-thione      benzodiazepin-5-one                                    69.   7-methoxy-5-phenyl-1H-                                                                           8-methoxy-6-phenyl-4H-                                       1,5-benzodiazepin-4-                                                                             s-triazolo[4,3-a][1,5]-                                      one-2-thione      benzodiazepin-5-one                                    70.   7-(methylthio)-5-phenyl-                                                                         8-(methylthio)-6-phenyl-                                     1H-1,5-benzodiazepin-                                                                            4H-s-triazolo[4,3-a][1,5]-                                   4-one-2-thione    benzodiazepin-5-one                                    71.   7-pentyl-5-phenyl-1H-                                                                            8-pentyl-6-phenyl-4H-                                        1,5-benzodiazepin-4-                                                                             s-triazolo[4,3-a][1,5]-                                      one-2-thione      benzodiazepin-5-one                                    72.   7-pentoxy-5-phenyl-1H-                                                                           8-pentoxy-6-phenyl-4H-                                       1,5-benzodiazepin-4-                                                                             s-triazolo[4,3-a][1,5]-                                      one-2-thione      benzodiazepin-5-one                                    73.   7-bromo-5-phenyl-1H-                                                                             8-bromo-6-phenyl-4H-                                         1,5-benzodiazepin-4-                                                                             s-triazolo[4,3-a][1,5]-                                      one-2-thione      benzodiazepin-5-one                                    74.   7-fluoro-5-phenyl-1H-                                                                            8-fluoro-6-phenyl-4H-                                        1,5-benzodiazepin-4-                                                                             s-triazolo[4,3-a][1,5]-                                      one-2-thione      benzodiazepin-5-one                                    75.   7-cyano-5-phenyl-1H-                                                                             8-cyano-6-phenyl-4H-                                         1,5-benzodiazepin-4-                                                                             s-triazolo[4,3-a][1,5]-                                      one-2-thione      benzodiazepin-5-one                                    76.   7-chloro-5-(2-chloro-                                                                            8-chloro-6-(2-chloro-                                        phenyl)-1H-1,5-benzo-                                                                            phenyl)-4H-s-triazolo-                                       diazepin-4-one-2- [4,3-a][1,5]benzodia-                                        thione            zepin-5-one                                            77.   7-chloro-5-(2-fluoro-                                                                            8-chloro-6-(2-fluoro-                                        phenyl)-1H-1,5-benzo-                                                                            phenyl)-4H-s-triazolo-                                       diazepin-4-one-2- [4,3-a][1,5]benzodia-                                        thione            zepin-5-one                                            78.   7-chloro-5-(3-chloro-                                                                            8-chloro-6-(3-chloro-                                        phenyl)-1H-1,5-benzo-                                                                            phenyl)-4H-s-triazolo-                                       diazepin-4-one-2- [4,3-a][1,5]benzodia-                                        thione            zepin-5-one                                            79.   7-chloro-5-(4-chloro-                                                                            8-chloro-6-(4-chloro-                                        phenyl)-1H-1,5-benzo-                                                                            phenyl)-4H-s-triazolo-                                       diazepin-4-pne-2- [4,3-a][1,5]benzodia-                                        thione            zepin-5-one                                            80.   7-chloro-5-(2-methoxy-                                                                           8-chloro-6-(2-methoxy-                                       phenyl)-1H-1,5-benzo-                                                                            phenyl)-4H-s-triazolo-                                       diazepin-4-one-2- [4,3-a][1,5]benzodia-                                        thione            zepin-5-one                                            81.   7-chloro-5-(3-methoxy-                                                                           8-chloro-6-(3-methoxy-                                       phenyl-1H-1,5-benzo-                                                                             phenyl)-4H-s-triazolo-                                       diazepin-4-one-2- [4,3-a][1,5]benzodia-                                        thione            zepin-5-one                                            82.   7-chloro-5-(4-methoxy-                                                                           8-chloro-6-(4-methoxy-                                       phenyl)-1H-1,5-benzo-                                                                            phenyl)-4H-s-triazolo-                                       diazepin-4-one-2- [4,3-a][1,5]benzodia-                                        thione            zepin-5-one                                            83.   7-chloro-5-(2-methyl-                                                                            8-chloro-6-(2-methyl-                                        phenyl)-1H-1,5-benzo-                                                                            phenyl)-4H-s-triazolo-                                       diazepin-4-one-2- [4,3-a][1,5]benzodia-                                        thione            zepin-5-one                                            84.   7-chloro-5-(3-methyl-                                                                            8-chloro-6-(3-methyl-                                        phenyl)-1H-1,5-benzo-                                                                            phenyl)-4H-s-triazolo-                                       diazepin-4-one-2- [4,3-a][1,5]benzodia-                                        thione            zepin-5-one                                            85.   7-chloro-5-(4-methyl-                                                                            8-chloro-6-(4-methyl-                                        phenyl)-1H-1,5-benzo-                                                                            phenyl-4H-s-triazolo-                                        diazepin-4-one-2-thione                                                                          [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            86.   3-methyl-7-chloro-5-                                                                             4-methyl-8-chloro-6-                                         phenyl-1H-1,5-benzo-                                                                             phenyl-4H-s-triazolo-                                        diazepin-4-one-2- [4,3-a][1,5]benzodia-                                        thione            zepin-5-one                                            87.   3-(benzyloxy)-7-chloro-                                                                          4-(benzyloxy)-8-chloro-                                      5-phenyl-1H-1,5-benzo-                                                                           6-phenyl-4H-s-triazolo                                       diazepin-4-one-2- [4,3-a][1,5]benzodia-                                        thione            zepin-5-one                                            88.   3-methoxy-7-chloro-                                                                              4-methoxy-8-chloro-6-                                        5-phenyl-1H-1,5-benzo-                                                                           phenyl-4H-s-triazolo-                                        diazepin-4-one-2- [4,3-a][1,5]benzodia-                                        thione            zepin-5-one                                            89.   8-methyl-5-phenyl-1H-                                                                            9-methyl-6-phenyl-4H-                                        1,5-benzodiazepin-4-one-                                                                         s-triazolo[4,3-a][1,5]-                                      2-thione          benzodiazepin-5-one                                    90.   8-chloro-5-phenyl-1H-                                                                            9-chloro-6-phenyl-4H-                                        1,5-benzodiazepin-4-                                                                             s-triazolo[4,3-a][1,5]-                                      one-2-thione      benzodiazepin-5-one                                    91.   8-(trifluoromethyl)-                                                                             9-(trifluoromethyl)-6-                                       5-phenyl-1H-1,5-benzo-                                                                           phenyl-4H-s-triazolo-                                        diazepin-4-one-2- [4,3-a][1,5]benzodia-                                        thione            zepin-5-one                                            ______________________________________                                    

EXAMPLE 92 2-(Methylthio)-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one

To 3.03 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione in a solution of 0.40 g sodium hydroxide and 15 ml of methanol is added, with stirring a solution of 1.39 g of methyl iodide in 5 ml of methanol. Stirring is continued for 1 hour, the reaction is evaporated, diluted with 30 ml methylene chloride and filtered through a short Florisil column. After washing the column with ethyl acetate, the combined filtrates are evaporated to give the title compound.

EXAMPLES 93 - 96

Following the procedure of Example 92 but substituting the compounds indicated in column I below for methyl iodide and the compounds indicated in column II for 7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione in Example 92, the benzodiazepinones indicated in column III are obtained.

    __________________________________________________________________________     I              II               III                                            __________________________________________________________________________        benzylbromide                                                                            7-(trifluoromethyl)-5-phenyl-                                                                  2-(benzylthio)-7-(trifluoromethyl)-                            1H-1,5-benzodiazepin-4-one-                                                                    5-phenyl-3H-1,5-benzodiazepin-                                 2-thione        4-one                                                O-propyl p-toluene-                                                                      7-nitro-5-(o-chlorophenyl)-                                                                    2-(propylthio)-7-nitro-5-(o-                         sulfonate 1H-1,5-benzodiazepin-4-one-                                                                    chlorophenyl)-3H-1,5-benzodia-                                 2-thione        zepin-4-one                                          methyl iodide                                                                            7-(trifluoromethyl)-5-phenyl-                                                                  2-(methylthio)-7-(trifluoromethyl)-                            1H-1,5-benzodiazepin-4-one-                                                                    5-phenyl-3H-1,5-benzodiazepin-                                 2-thione        4-one                                                dimethyl sulfate                                                                         7-chloro-5-benzyl-1H-1,5-                                                                      2-(methylthio)-7-chloro-                                       benzodiazepin-4-one-2-thione                                                                   5-benzyl-3H-1,5-benzodiazepin-                                                 4-one                                             __________________________________________________________________________

EXAMPLES 97 - 102

Following the procedure of Example 92 but substituting the compounds indicated in Column I below for 7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione in Example 92, the compounds indicated in Column II are obtained.

    ______________________________________                                           I                   II                                                       ______________________________________                                         97.    5-phenyl-1H-1,5- 2-(methylthio)-5-phenyl-                                      benzodiazepin-4-one-                                                                            3H-1,5-benzodiazepin-                                         2-thione         4-one                                                  98.    7-(trifluoromethyl)-5-                                                                          2-(methylthio)-7-(tri-                                        phenyl-1H-1,5-benzo-                                                                            fluoromethyl)-5-phenyl-                                       diazepin-4-one-2-                                                                               3H-1,5-benzodiazepin-                                         thione           4-one                                                  99.    7-nitro-5-phenyl-                                                                               2-(methylthio)-7-nitro-                                       1H-1,5-benzodiaze-                                                                              5-phenyl-3H-1,5-benzo-                                        pin-4-one-2-thione                                                                              diazepin-4-one                                         100.   7-methyl-5-phenyl-1H-                                                                           2-(methylthio)-7-methyl-                                      1,5-benzodiazepin-4-                                                                            5-phenyl-3H-1,5-benzo-                                        one-2-thione     diazepin-4-one                                         101.   7-methoxy-5-phenyl-                                                                             2-(methylthio)-7-methoxy-                                     1H-1,5-benzodiazepin-                                                                           5-phenyl-3H-1,5-benzo-                                        4-one-2-thione   diazepin-4-one                                         102.   7-(methylthio)-5-                                                                               2-(methylthio)-7-(methyl-                                     phenyl-1H-1,5-benzo-                                                                            thio)-5-phenyl-3H-1,5-                                        diazepin-4-one-2-                                                                               benzodiazepin-4-one                                           thione                                                                  ______________________________________                                    

EXAMPLES 103 - 109

Following the procedure of Example 29, Method B, but substituting the compounds indicated in Column I below for acetic acid hydrazide in Example 29, Method B, the compounds indicated in Column II are obtained.

    ______________________________________                                                I              II                                                       ______________________________________                                         103.   N,N-dimethylglycine-                                                                            1-[(Dimethylamino)-                                           hydrazide        methyl]-8-chloro-6-                                                            phenyl-4H-s-triazolo-                                                          [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            104.   N,N-diethylglycine-                                                                             1-[(Diethylamino)-                                            hydrazide        methyl]-8-chloro-6-                                                            phenyl-4H-s-triazolo-                                                          [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            105.   Pyrrolidinoacetic                                                                               1-[(1-Pyrrolidino)-                                           acid hydrazide   methyl]-8-chloro-6-                                                            phenyl-4H-s-triazolo-                                                          [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            106.   4-Morpholinoacetic                                                                              1-(4-Morpholinomethyl)-                                       acid hydrazide   8-chloro-6-phenyl-4H-                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                    107.   1-Piperidinoacetic acid                                                                         1-(1-Piperidinomethyl)-                                       hydrazide        8-chloro-6-phenyl-4H-                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                    108.   N-Methylglycine  1-[(Methylamino)-methyl]-                                     hydrazide        8-chloro-6-phenyl-4H-                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                    109.   2-(p-Methoxybenzyloxy)                                                                          1-[(p-Methoxybenzyloxy)-                                      acetic acid hydrazide                                                                           methyl]-8-chloro-6-                                                            phenyl-4H-s-triazolo-                                                          [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            ______________________________________                                    

EXAMPLES 110 - 115

Following the procedure of Example 29, Method B, but substituting the compounds indicated in Column I below for acetic acid hydrazide and the compounds indicated in Column II below for 2-(methylthio)-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one in Example 29, Method B, the compounds indicated in Column III are obtained.

    __________________________________________________________________________     I                 II                 III                                       __________________________________________________________________________     110.                                                                               formic acid hydrazide                                                                      2-(methylthio)-7-chloro-5-                                                                       8-chloro-6-benzyl-4H-s-triazolo-                             benzyl-3H-1,5-benzodia-                                                                          [4,3-a][1,5]benzodiazepin-5-                                 zepin-4-one       one                                          111.                                                                               acetic acid hydrazide                                                                      2-(methylthio)-7-chloro-5-                                                                       1-methyl-8-chloro-6-benzyl-4H-s-                             benzyl-3H-1,5-benzodia-                                                                          triazolo[4,3-a][1,5]benzodiazepin-                           zepin-4-one       5-one                                        112.                                                                               acetic acid hydrazide                                                                      2-(benzylthio)-7-(trifluoro-                                                                     1-methyl-8-(trifluoromethyl)-6-                              methyl)-5-phenyl-3H-1,5-                                                                         phenyl-4H-s-triazolo[4,3-a][1,5]-                            benzodiazepin-4-one                                                                              benzodiazepin-5-one                          113.                                                                               acetic acid hydrazide                                                                      2-(propylthio)-7-nitro-5-                                                                        1-methyl-8-nitro-6-(o-chloro-                                (o-chlorophenyl)-3H-1,5-                                                                         phenyl)-4H-s-triazolo[4,3-a] -                               benzodiazepin-4-one                                                                              [1,5]benzodiazepin-5-one                     114.                                                                               acetic acid hydrazide                                                                      2-(methylthio)-7-(trifluoro-                                                                     1-methyl-8-(trifluoromethyl)-6-                              methyl)-5-phenyl-3H-1,5-                                                                         phenyl-4H-s-triazolo[4,3-a]-                                 benzodiazepin-4-one                                                                              [1,5]benzodiazepin-5-one                     115.                                                                               acetic acid hydrazide                                                                      2-(methylthio)-7-(trifluoromethyl)-                                                              1-methyl-8-(trifluoromethyl)-6-                              5-benzyl-3H-1,5-benzodiazepin-                                                                   benzyl-4H-s-triazolo[4,3-a][1,5]-                            4-one             benzodiazepin-5-one                          __________________________________________________________________________

EXAMPLES 116 - 121

Following the procedure of Example 29, Method B, but substituting the compounds indicated in Column I below for 2-(methylthio)-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one in Example 29, Method B, the compounds indicated in Column II are obtained.

    ______________________________________                                         I                    II                                                        ______________________________________                                         116. 2-(methylthio)-5-phenyl                                                                         1-methyl-6-phenyl-4H-s-                                       3H-1,5-benzodiazepin-4-                                                                         triazolo[4,3-a][1,5]-                                         one              benzodiazepin-5-one                                      117. 2-(methylthio)-7-(tri-                                                                          1-methyl-8-(trifluoromethyl)-                                 fluoromethyl)-5-phenyl-                                                                         6-phenyl-4H-s-triazolo-                                       3H-1,5-benzodiazepin-                                                                           [4,3-a][1,5]benzodiazepin-                                    4-one            5-one                                                    118. 2-(methylthio)-7-nitro-                                                                         1-methyl-8-nitro-6-phenyl-                                    5-phenyl-3H-1,5-ben-                                                                            4H-s-triazolo[4,3-a][1,5]-                                    zodiazepin-4-one benzodiazepin-5-one                                      119. 2-(methylthio)-7-methyl-                                                                        1-methyl-8-methyl-6-phenyl-                                   5-phenyl-3H-1,5-ben-                                                                            4H-s-triazolo[4,3-a][1,5]-                                    zodiazepin-4-one benzodiazepin-5-one                                      120. 2-(methylthio)-7-methoxy-                                                                       1-methyl-8-methoxy-6-phenyl-                                  5-phenyl-3H-1,5-ben-                                                                            4H-s-triazolo[4,3-a][1,5]-                                    zodiazepin-4-one benzodiazepin-5-one                                      121. 2-(methylthio)-7-(methyl-                                                                       1-methyl-8-(methylthio)-6-                                    thio)-5-phenyl-3H-1,5-                                                                          phenyl-4H-s-triazolo[4,3-a]-                                  benzodiazepin-4-one                                                                             [1,5]benzodiazepin-5-                                                          one                                                      ______________________________________                                    

Example 122 1-(Hydroxymethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one

3.1 g of 1-[(p-methoxybenzyloxy)-methyl]-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 30 ml acetic acid, at 25°, is stirred with 24 ml 48% aqueous hydrobromic acid for 20 minutes. The reaction is neutralized with 30% aqueous sodium hydroxide and extracted with chloroform. The organic phase is separated, washed with water, dried and the solvent evaporated to give the title compound.

Example 123 1-(hydroxymethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one, methanesulfonate

3.4 g of 1-(hydroxymethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 30 ml chloroform is reacted with 3.03 g triethylamine and then 3.44 g methanesulfonyl chloride. The reaction is stirred at 20° for 90 minutes, washed with water, then with saturated aqueous sodium chloride and dried. The solvent is evaporated to give the title compound.

EXAMPLE 124 1-(Diethylaminomethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one

3.35 g of 1-(Hydroxymethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one, methanesulfonate in 15 ml dimethylsulfoxide at 0° is added dropwise with stirring to 3 ml of diethylamine in 10 ml dimethylsulfoxide. The reaction is stirred at 20° for 2 hours, diluted with methylene chloride, washed with water and then saturated aqueous sodium chloride. After drying, the solvent is evaporated to give the title compound.

EXAMPLES 125 - 132

Following the procedure of Example 124, but substituting the amines indicated in Column I below for diethylamine amine in Example 124, the compounds in Column II are obtained.

    ______________________________________                                         I               II                                                             ______________________________________                                         125.  ammonia     1-(aminomethyl)-8-chloro-                                                      6-phenyl-4H-s-triazolo-                                                        [4,3-a][1,5]benzodia-                                                          zepin-5-one                                                  126.  methylamine 1-(methylaminomethyl)-                                                         8-chloro-6-phenyl-4H-                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                          127.  dimethylamine                                                                              1-(dimethylaminomethyl)-                                                       8-chloro-6-phenyl-4H-                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                          128.  pyrrolidine 1-[(1-pyrrolidino)-                                                            methyl]-8-chloro-6-                                                            phenyl-4H-s-triazolo-                                                          [4,3-a][1,5]benzodia-                                                          zepin-5-one                                                  129.  morpholine  1-(4-morpholinomethyl)-                                                        8-chloro-6-phenyl-4H-                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                          130.  2-ethanolamine                                                                             1-[[(2-hydroxyethyl)-                                                          amino]-methyl]-8-                                                              chloro-6-phenyl-4H-s-                                                          triazolo[4,3-a][1,5]-                                                          benzodiazepin-5-one                                          131.  piperidine  1-(piperidinomethyl)-                                                          8-chloro-6-phenyl-4H-                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                          132.  benzylamine 1-[(benzylamino)-methyl]-                                                      8-chloro-6-phenyl-4H-                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                          ______________________________________                                    

EXAMPLE 133 2-Methoxy-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one

To 11.4 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione stirred in 150 ml methanol is added, dropwise, approximately 2.1 g of diazomethane in ether. After addition is complete, the reaction is stirred for 1 hour and filtered. The filtrate is evaporated and the residue diluted with a small amount of ether. The suspension is filtered and the filtrate evaporated to give the title compound.

EXAMPLE 134 1-[[(Benzyloxycarbonyl)-amino]-methyl]-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one

9.0 g of 2-methoxy-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one and 6.69 g of 1-[(benzyloxycarbonyl)amino]acetic acid hydrazide in 210 ml n-butanol and 50 ml dimethyl sulfoxide are heated at 140° for 9 hours. The reaction is evaporated and the residue is worked up as described in Example 29, Method D, to give the title compound.

EXAMPLE 135 1-(Aminomethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a]-[1,5]benzodiazepin-5-one

4.5 g of 1-[[(benzyloxycarbonyl)amino]-methyl]-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 60 ml acetic acid saturated with hydrogen bromide is stirred at 20° for 1 hour. The reaction mixture is concentrated to one-half its original volume in vacuo and diluted with ether. The precipitate is filtered off, suspended in methylene chloride and shaken with excess 2N aqueous sodium bicarbonate. The organic phase is separated, washed with water, dried and evaporated to give the title compound.

EXAMPLE 136 1-(Acetoxymethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one

3.4 g of 1-(hydroxymethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one and 1.0 g of acetic anhydride in 10 ml of pyridine are warmed in a steam bath for 0.2 hour and stirred at room temperature for 10 hours. The reaction mixture is cooled, diluted with 100 ml methylene chloride and washed with 100 ml water containing 0.84 g sodium bicarbonate. The organic phase is washed four times with water, dried and evaporated. The residue is triturated with a minimum amount of ether and the title compound filtered off, dried and recrystallized from methylene chloride and ether.

Example 137 4-Acetoxy-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one

6.2 g of 8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one, 3 g of N-chlorosuccinimide and 0.1 g of azodiisobutyronitrile in 200 ml benzene are refluxed for 1 hour. The solvent is evaporated and the residue (which contains 4,8-dichloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one) is heated on a steam-bath for 10 minutes with 90 g of glacial acetic acid and 2.5 g of sodium acetate. The reaction is evaporated and the residue partitioned between chloroform and dilute aqueous sodium bicarbonate. The chloroform is washed with water, dried and the solvent evaporated to give the title compound.

EXAMPLE 138 4-Ethoxy-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one

Following the procedure of Example 137 but substituting ethanol for both the glacial acetic acid and the sodium acetate in Example 137. the title compound is obtained.

EXAMPLE 139 4-Hydroxy-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one

3.5 g of 4-acetoxy-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one and 2.8 ml of 4N aqueous sodium hydroxide in 160 ml of ethanol are stirred overnight at 25°. The reaction is neutralized with 0.5 g of acetic acid and the solvent is evaporated. The residue is partitioned between chloroform and water, the organic phase is dried and the solvent evaporated to give the title compound.

EXAMPLE 140 7-Chloro-5-benzyl-1H-1,5-benzodiazepine-2,4-dione Method A

To a stirred refluxing solution of 22.3 g of 2-benzylamino-4-chloroaniline in 400 ml benzene is added, dropwise, a solution of 13.8 g of malonyl dichloride in 45 ml benzene. After addition is complete the reaction was refluxed for 7 hours, concentrated to 1/2 the original volume and cooled. The title compound is filtered off and dried. The filtrate is evaporated and the residue recrystallized from a mixture of ethanol-dimethylformamide to give additional product.

Method B

9.2 g of N-benzyl-N-(2'-amino-5'-chloro-phenyl)-malonamic acid, ethyl ester is added to a solution of 0.73 g of sodium in 100 ml ethanol. After refluxing for 2 hours the reaction is evaporated, the residue dissolved in water and acidified with hydroacetic acid. The title compound is filtered off and dried.

Method C

30 g of N-benzyl-N-(2'-nitro-5'-chloro-phenyl)-malonamic acid ethyl ester is added to a stirred suspension of 59 g iron powder, 360 ml of ethanol, 150 ml acetic acid and 105 ml water at reflux. After two hours, the reaction is filtered and the filtrate evaporated. The residue is treated with dilute aqueous ammonium hydroxide, extracted with methylene chloride, washed with water and dried. The solvent is evaporated and the residue treated with ethanolic potassium hydroxide. The ethanol is evaporated, the residue taken up in water and acidified to pH 6 with hydrochloric acid. The title compound is filtered off and dried.

Method D

11 g of N-benzyl-N-(2'-amino-5'-chloro-phenyl)-malonamic acid ethyl ester in 50 ml ethanol containing 1.7 g potassium hydroxide is kept at room temperature for 6 hours, refluxed for 45 minutes and the solvent evaporated. The residue is taken up in water, neutralized to pH 7 with hydrochloric acid and the title compound filtered off and dried.

EXAMPLES 141 - 151

Following the procedure of Example 140, Method A, but substituting the compounds indicated in Column I below for 2-benzylamino-4-chloroaniline in Example 140, Method A, the compounds in Column II are obtained.

    ______________________________________                                         I                   II                                                         ______________________________________                                         141. 2-benzylamino-4-  7-(trifluoromethyl)-5-                                       (trifluoromethyl)aniline                                                                         benzyl-1H-1,5-benzodia-                                                        zepine-2,4-dione                                        142. 2-benzylamino-4- 7-methyl-5-benzyl-1H-                                         methylaniline     1,5-benzodiazepine-                                                            2,4-dione                                               143. 2-benzylamino-aniline                                                                            5-benzyl-1H-1,5-benzo-                                                         diazepine-2,4-dione                                     144. 2-benzylamino-4-  7-methoxy-5-benzyl-1H-                                       methoxyaniline    1,5-benzodiazepine-                                                            2,4-dione                                               145. 2-benzylamino-5-  8-chloro-5-benzyl-1H-                                        chloroaniline     1,5-benzodiazepine-                                                            2,4-dione                                               146. 2-benzylamino-5-  8-(trifluoromethyl)-5-                                       (trifluoromethyl)aniline                                                                         benzyl-1H-1,5-benzo-                                                           diazepine-2,4-dione                                     147. 2-(p-methoxybenzyl-                                                                              7-chloro-5-(p-methoxy-                                       amino)-4-chloroaniline                                                                           benzyl)-1H-1,5-benzodia-                                                       zepine-2,4-dione                                        148. 2-(p-methoxybenzyl-                                                                              7-nitro-5-(p-methoxy-                                        amino)-4-nitroaniline                                                                            benzyl)-1H-1,5-benzo-                                                          diazepine-2,4-dione                                     149. 2-(p-methoxybenzyl-                                                                              7-methoxy-5-(p-methoxy-                                      amino)-4-methoxy- benzyl)-1H-1,5-benzo-                                        aniline           diazepine-2,4-dione                                     150. 2-(p-methoxypenzyl-                                                                              7-methyl-5-(p-methoxy-                                       amino)-4-methyl-  benzyl)-1H-1,5-benzo-                                        aniline           diazepine-2,4-dione                                     151. 2-(o,p-dimethoxy- 7-(trifluoromethyl)-5-                                       benzylamino)-4-   (o,p-dimethoxybenzyl)-                                       (trifluoromethyl) 1H-1,5-benzodiazepine-                                       methylaniline     2,4-dione                                               ______________________________________                                    

EXAMPLES 152-164

Following the procedure of Example 1 but substituting the compounds indicated in Column 1 below for 7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione in Example 1, the compounds indicated in Column II are obtained.

    ______________________________________                                         I                   II                                                         ______________________________________                                         152. 5-benzyl-1H-1,5-benzo-                                                                           5-benzyl-1H-1,5-benzo-                                       diazepine-2,4-dione                                                                              diazepin-4-one-2-thione                                 153. 7-chloro-5-benzyl-1H-                                                                            7-chloro-5-benzyl-                                           1,5-benzodiazepine-                                                                              1H-1,5-benzodiazepin-                                        2,4-dione         4-one-2-thione                                          154. 7-methyl-5-benzyl-1H-                                                                            7-methyl-5-benzyl-1H-                                        1,5-benzodiazepine-                                                                              1,5-benzodiazepin-4-                                         2,4-dione         one-2-thione                                            155. 7-methoxy-5-benzyl-1H-                                                                           7-methoxy-5-benzyl-1H-                                       1,5-benzodiazepine-                                                                              1,5-benzodiazepin-4-                                         2,4-dione         one-2-thione                                            156. 8-(trifluoromethyl)-5-                                                                           8-(trifluoromethyl)-5-                                       benzyl-1H-1,5-benzodia-                                                                          benzyl-1H-1,5-benzo-                                         zepine-2,4-dione  diazepin-4-one-2-thione                                 157. 8-chloro-5-benzyl-1H-                                                                            8-chloro-5-benzyl-1H-                                        1,5-benzodiazepine-                                                                              1,5-benzodiazepin-4-                                         2,4-dione         one-2-thione                                            158. 7-(trifluoromethyl)-5-                                                                           7-(trifluoromethyl)-5-                                       benzyl-1H-1,5-benzo-                                                                             benzyl-1H-1,5-benzo-                                         diazepine-2,4-dione                                                                              diazepin-4-one-2-thione                                 159. 7-chloro-5-(p-methoxy-                                                                           7-chloro-5-(p-methoxy-                                       benzyl)-1H-1,5-benzo-                                                                            benzyl)-1H-1,5-benzo-                                        diazepine-2,4-dione                                                                              diazepin-4-one-2-                                                              thione                                                  160. 7-nitro-5-(p-methoxy-                                                                            7-nitro-5-(p-methoxy-                                        benzyl)-1H-1,5-benzo-                                                                            benzyl)-1H-1,5-benzo-                                        diazepine-2,4-dione                                                                              diazepin-4-one-2-                                                              thione                                                  161. 7-methoxy-5-(p-methoxy-                                                                          7-methoxy-5-(p-methoxy-                                      benzyl)-1H-1,5-benzo-                                                                            benzyl)-1H-1,5-benzo-                                        diazepine-2,4-dione                                                                              diazepin-4-one-2-                                                              thione                                                  162. 7-methyl-5-(p-methoxy-                                                                           7-methyl-5-(p-methoxy-                                       benzyl)-1H-1,5-benzo-                                                                            benzyl)-1H-1,5-benzo-                                        diazepine-2,4-dione                                                                              diazepin-4-one-2-                                                              thione                                                  163. 7-(trifluoromethyl)-5-                                                                           7-(trifluoromethyl)-5-                                       (p-methoxybenzyl)-1H-                                                                            (p-methoxybenzyl)-                                           1,5-benzodiazepine-2,4-                                                                          1H-1,5-benzodiazepin-                                        dione             4-one-2-thione                                          164. 7-(trifluoromethyl)-5-                                                                           7-(trifluoromethyl)-5-                                       (o,p-dimethoxybenzyl)-                                                                           (o,p-dimethoxybenzyl)-                                       1H-1,5-benzodiazepine-                                                                           1H-1,5-benzodiazepin-                                        2,4-dione         4-one-2-thione                                          ______________________________________                                    

Examples 165 - 177

Following the procedure of Example 29, Method A, but substituting the compounds indicated in Column I below for 7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione in Example 29, Method A, the compounds indicated in Column II are obtained.

    ______________________________________                                         I                    II                                                        ______________________________________                                         165.  5-benzyl-1H-1,5-benzo-                                                                           1-methyl-6-benzyl-4H-                                        diazepin-4-one-2-thione                                                                          s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                    166.  7-chloro-5-benzyl-1H-                                                                            1-methyl-8-chloro-6-                                         1,5-benzodiazepin-4-one-                                                                         benzyl-4H-s-triazolo-                                        2-thione          [4,3-2][1,5]benzodia-                                                          zepin-5-one                                            167.  7-methyl-5-benzyl-1H-                                                                            1-methyl-8-methyl-6-                                         1,5-benzodiazepin-4-                                                                             benzyl-4H-s-triazolo-                                        one-2-thione      [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            168.  7-methoxy-5-benzyl-1H-                                                                           1-methyl-8-methoxy-6-                                        1,5-benzodiazepin-4-                                                                             benzyl-4H-s-triazolo-                                        one-2-thione      [4,3-2][1,5]benzodia-                                                          zepin-5-one                                            169.  8-(trifluoromethyl)-5-                                                                           1-methyl-9-(trifluoro-                                       benzyl-1H-1,5-benzodia-                                                                          methyl)-6-benzyl-4H-s-                                       zepin-4-one-2-thione                                                                             triazolo[4,3-a][1,5]-                                                          benzodiazepin-5-one                                    170.  8-chloro-5-benzyl-1H-                                                                            1-methyl-9-chloro-6-                                         1,5-benzodiazepin-4-                                                                             benzyl-4H-s-triazolo-                                        one-2-thione      [4,3-a][1,5]benzo-                                                             diazepin-5-one                                         171.  7-(trifluoromethyl)-5-                                                                           1-methyl-8-(trifluoro-                                       benzyl-1H-1,5-benzodia-                                                                          methyl)-6-benzyl-4H-s-                                       zepin-4-one-2-thione                                                                             triazolo[4,3-a][1,5]-                                                          benzodiazepin-5-one                                    172.  7-chloro-5-(p-methoxy-                                                                           1-methyl-8-chloro-6-                                         benzyl)-1H-1,5-benzo-                                                                            (p-methoxybenzyl)-4H-                                        diazepin-4-one-2- s-triazolo[4,3-a][1,5]-                                      thione            benzodiazepin-5-one                                    173.  7-nitro-5-(p-methoxy-                                                                            1-methyl-8-nitro-6-                                          benzyl)-1H-1,5-benzo-                                                                            (p-methoxybenzyl)-4H-                                        diazepin-4-one-2- s-triazolo[4,3-a][1,5]-                                      thione            benzodiazepin-5-one                                    174.  7-methoxy-5-(p-methoxy-                                                                          1-methyl-8-methoxy-6-                                        benzyl)-1H-1,5-benzo-                                                                            (p-methoxybenzyl)-4H-                                        diazepin-4-one-2- s-triazolo[4,3-a][1,5]-                                      thione            benzodiazepin-5-one                                    175.  7-methyl-5-(p-methoxy-                                                                           1-methyl-8-methyl-6-                                         benzyl)-1H-1,5-benzo-                                                                            (p-methoxybenzyl)-4H-                                        diazepin-4-one-2- s-triazolo[4,3-a][1,5]-                                      thione            benzodiazepin-5-one                                    176.  7-(trifluoromethyl)-5-                                                                           1-methyl-8-(trifluoro-                                       (p-methoxybenzyl)-1H-                                                                            methyl)-6-(p-methoxy-                                        1,5-benzodiazepin-4-one-                                                                         benzyl)-4H-s-triazolo                                        2-thione          [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            177.  7-(trifluoromethyl)-5-                                                                           1-methyl-8-(trifluoro-                                       (o,p-dimethoxybenzyl)-                                                                           methyl)-6-(o,p-dimethoxy-                                    1H-1,5-benzodiazepin-                                                                            benzyl)-4H-s-triazolo-                                       4-one-2-thione    [4,3-a][1,5]benzodia-                                                          zepin-5-one                                            ______________________________________                                    

EXAMPLES 178 - 189

Following the procedure of Example 29, Method A, but substituting the acid hydrazides indicated in Column I below for acetic acid hydrazide and the compounds indicated in column II below for 7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione in Example 29, Method A, the compounds in Column III are obtained:

    __________________________________________________________________________     I                II               III                                          __________________________________________________________________________     178.                                                                              formic acid hydrazide                                                                       7-chloro-5-benzyl-1H-1,5-benzo-                                                                 8-chloro-6-benzyl-4H-s-triazolo-                              diazepin-4-one-2-thione                                                                         [4,3-a][1,5]benzodiazepin-5-one               179.                                                                              propionic acid hydra-                                                                       7-chloro-5-benzyl-1H-1,5-benzo-                                                                 1-ethyl-8-chloro-6-benzyl-4H-s-                  zide         diazepin-4-one-2-thione                                                                         triazolo[4,3-a][1,5]benzodia-                                                  zepin-5-one                                   180.                                                                              cyclopropane carboxylic                                                                     7-chloro-5-benzyl-1H-1,5-benzo-                                                                 1-cyclopropyl-8-chloro-6-                        acid hydrazide                                                                              diazepin-4-one-2-thione                                                                         benzyl-4H-s-triazolo[4,3-a]-                                                   [1,5]benzodiazepin-5-one                      181.                                                                              N,N-dimethyl-                                                                               7-chloro-5-benzyl-1H-1,5-benzo-                                                                 1-[(dimethylamino)methyl]-8-                     aminoglycine hydrazide                                                                      diazepin-4-one-2-thione                                                                         chloro-6-benzyl-4H-s-triazolo-                                                 [4,3-a][1,5]benzodiazepin-5-                                                   one                                           182.                                                                              formic acid  7-(trifluoromethyl)-5-(p-                                                                       8-(trifluoromethyl)-6-(p-methoxy-                hydrazide    methoxybenzyl)-1H-1,5-benzo-                                                                    benzyl)-4H-s-triazolo[4,3-a]-                                 diazepin-4-one-2-thione                                                                         [1,5]benzodiazepin-5-one                      183.                                                                              propionic acid                                                                              7-(trifluoromethyl)-5-(p-                                                                       1-ethyl-8-(trifluoromethyl)-6-                   hydrazide    methoxybenzyl)-1H-1,5-benzo-                                                                    (p-methoxybenzyl)-4H-s-triazolo-                              diazepin-4-one-2-thione                                                                         [4,3-a][1,5]benzodiazepin-5-one               184.                                                                              cyclopropane 7-(trifluoromethyl)-5-(p-                                                                       1-cyclopropyl-8-(trifluoromethyl)-               carboxylic acid                                                                             methoxybenzyl)-1H-1,5-benzo-                                                                    6-(p-methoxybenzyl)-4H-s-                        hydrazide    diazepin-4-one-2-thione                                                                         triazolo[4,3-a][1,5]benzodia-                                                  zepin-5-one                                   185.                                                                              N,N-dimethyl-                                                                               7-(trifluoromethyl)-5-(p-                                                                       1-[(dimethylamino)methyl]-8-                     aminoglycine methoxybenzyl)-1H-1,5-benzo-                                                                    (trifluoromethyl)-6-(p-methoxy-                  hydrazide    diazepin-4-one-2-thione                                                                         benzyl)-4H-s-triazolo[4,3-a]-                                                  [1,5]benzodiazepin-5-one                      186.                                                                              formic acid  7-nitro-5-(p-methoxybenzyl)-                                                                    8-nitro-6-(p-methoxybenzyl)-                     hydrazide    1H-1,5-benzodiazepin-4-one-                                                                     4H-s-triazolo[ 4,3-a][1,5]-                                   2-thione         benzodiazepin-5-one                           187.                                                                              propionic acid                                                                              7-nitro-5-(p-methoxybenzyl)-                                                                    1-ethyl-8-nitro-6-(p-methoxy-                    hydrazide    1H-1,5-benzodiazepin-4-one-                                                                     benzyl)-4H-s-triazolo[4,3-a]-                                 2-thione         [1,5]benzodiazepin-5-one                      188.                                                                              cyclopropane 7-nitro-5-(p-methoxybenzyl)-                                                                    1-cyclopropyl-8-nitro-6-                         carboxylic acid                                                                             1H-1,5-benzodiazepin-4-one-                                                                     (p-methoxybenzyl)-4H-s-tria-                     hydrazide    2-thione         zolo[4,3-a][1,5]benzodiazepin-                                                 5-one                                         189.                                                                              N,N-dimethyl-                                                                               7-nitro-5-(p-methoxybenzyl)-                                                                    1-[(dimethylamino)methyl]-8-                     aminoglycine 1H-1,5-benzodiazepin-4-one-                                                                     nitro-6-(p-methoxybenzyl)-                       hydrazide    2-thione         4H-s-triazolo[4,3-a][1,5]-                                                     benzodiazepin-5-one                           __________________________________________________________________________

EXAMPLE 190 8-Chloro-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one Method A

2.92 g of 8-chloro-6-benzyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 300 ml acetic acid containing 0.3 g of pre-reduced Raney nickel catalyst is hydrogenated at 60° starting with an initial hydrogen pressure of 60 p.s.i. The reduction is stopped after 0.01 mole of hydrogen has been absorbed, the catalyst filtered off and the solvent evaporated. The residue is stirred with water and the title compound is filtered off and dried.

Method B

2.92 g of 8-chloro-6-(p-methoxybenzyl)-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 100 ml of anhydrous hydrogen fluoride is stirred at 20° C for one hour. The hydrogen fluoride is then evaporated; the residue is partitioned between methylene chloride and dilute aqueous sodium bicarbonate. The organic phase is washed with water, dried and evaporated. The residue is stirred with ether and the title compound is filtered off and dried.

EXAMPLES 191 - 201

Following the procedure of Example 190, Method A, but substituting the compounds indicated in Column I below for 8-chloro-6-benzyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in Example 190, Method A, the compounds indicated in Column II are obtained.

    ______________________________________                                         I                    II                                                        ______________________________________                                         191.  1-methyl-6-benzyl-4H-s-                                                                          1-methyl-4H-s-triazolo-                                      triazolo[4,3-a][1,5]ben-                                                                         [4,3-a][1,5]benzodia-                                        zodiazepin-5-one  zepin-5-one                                            192.  1-methyl-8-chloro-6-                                                                             1-methyl-8-chloro-4H-                                        benzyl-4H-s-triazolo-                                                                            s-triazolo [4,3-a][1,5]-                                     [4,3-a][1,5]benzodia-                                                                            benzodiazepin-5-one                                          zepin-5-one                                                              193.  1-methyl-8-methyl-6-                                                                             1-methyl-8-methyl-4H-                                        benzyl-4H-s-triazolo-                                                                            s-triazolo [4,3-a][1,5]-                                     [4,3-a][1,5]benzodia-                                                                            benzodiazepin-5-one                                          zepin-5-one                                                              194.  1-methyl-8-methoxy-                                                                              1-methyl-8-methoxy-                                          6-benzyl-4H-s-triazolo-                                                                          4H-s-triazolo [4,3-a]-                                       [4,3-a][1,5]benzodia-                                                                            [1,5]benzodiazepin-5-                                        zepin-5-one       one                                                    195.  1-methyl-9-(trifluoro-                                                                           1-methyl-9-(trifluoro-                                       methyl)-6-benzyl-4H-                                                                             methyl)-4H-s-triazolo-                                       s-triazolo[4,3-a]-                                                                               [4,3-a][1,5]benzodia-                                        [1,5]benzodiazepin-                                                                              zepin-5-one                                                  5-one                                                                    196.  1-methyl-9-chloro-6-                                                                             1-methyl-9-chloro-                                           benzyl-4H-s-triazolo-                                                                            4H-s-triazolo[4,3-a]-                                        [4,3-a][1,5]benzodia-                                                                            [1,5]benzodiazepin-                                          zepin-5-one       5-one                                                  197.  1-methyl-8-(trifluoro-                                                                           1-methyl-8-(trifluoro-                                       methyl)-6-benzyl-4H-                                                                             methyl)-4H-s-triazolo-                                       s-triazolo[4,3-a]-                                                                               [4,3-a][1,5]benzodia-                                        [1,5]benzodiazepin-                                                                              zepin-5-one                                                  5-one                                                                    198.  8-chloro-6-benzyl-4H-                                                                            8-chloro-4H-s-triazolo-                                      s-triazolo[4,3-a][1,5]-                                                                          [4,3-a][1,5]benzodia-                                        benzodiazepin-5-one                                                                              zepin-5-one                                            199.  1-ethyl-8-chloro-6-                                                                              1-ethyl-8-chloro-4H-                                         benzyl-4H-s-triazolo-                                                                            s-triazolo[4,3-a][1,5]-                                      [4,3-a][1,5]benzo-                                                                               benzodiazepin-5-one                                          diazepin-5-one                                                           200.  1-cyclopropyl-8-chloro-                                                                          1-cyclopropyl-8-chloro-                                      6-benzyl-4H-s-triazolo-                                                                          4H-s-triazolo[4,3-a]-                                        [4,3-a][1,5] benzodia-                                                                           [1,5]benzodiazepin-5-                                        zepin-5-one       one                                                    201.  1-[(dimethylamino)-                                                                              1-[(dimethylamino)-                                          methyl]-8-chloro-6-                                                                              methyl]-8-chloro-4H-                                         benzyl-4H-s-triazolo-                                                                            s-triazolo[4,3-a][1,5]-                                      [4,3-a][1,5]benzodia-                                                                            benzodiazepin-5-one                                          zepin-5-one                                                              ______________________________________                                    

Examples 202 - 215

Following the procedure of Example 190, Method B, but substituting the compounds indicated in Column I below for 8-chloro-6-(p-methoxybenzyl)-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in Examples 190, Method B, the compounds indicated in Column II are obtained.

    ______________________________________                                         I                     II                                                       ______________________________________                                         202.  8-(trifluoromethyl)-6-                                                                            8-(trifluoromethyl)-4H-                                     (p-methoxybenzyl)-4H-                                                                             s-triazolo[4,3-a][1,5]-                                     s-triazolo[4,3-a][1,5]-                                                                           benzodiazepin-5-one                                         benzodiazepin-5-one                                                      203.  1-ethyl-8-(trifluoro-                                                                             1-ethyl-8-(trifluoro-                                       methyl)-6-(p-methoxy-                                                                             methyl)-4H-s-triazolo-                                      benzyl)-4H-s-triazolo-                                                                            [4,3-a][1,5]benzodia-                                       [4,3-a][1,5]benzodia-                                                                             zepin-5-one                                                 zepin-5-one                                                              204.  1-cyclopropyl-8-(tri-                                                                             1-cyclopropyl-8-(tri-                                       fluoromethyl)-6-(p-                                                                               fluorometyl)-4H-s-                                          methoxybenzyl)-4H-s-                                                                              triazolo[4,3-a][1,5]-                                       triazolo[4,3-a][1,5]-                                                                             benzodiazepin-5-one                                         benzodiazepin-5-one                                                      205.  1-[(dimethylamino)-                                                                               1-[(dimethylamino)-                                         methyl]-8-(trifluoro-                                                                             methyl]-8-(trifluoro-                                       methyl)-6-(p-methoxy-                                                                             methyl)-4H-s-triazolo-                                      benzyl-4H-s-triazolo-                                                                             [4,3-a][1,5]benzodia-                                       [4,3-a][1,5]benzodia-                                                                             zepin-5-one                                                 zepin-5-one                                                              206.  8-nitro-6-(p-methoxy-                                                                             8-nitro-4H-s-triazolo-                                      benzyl)-4H-s-triazolo-                                                                            [4,3-a][1,5]benzodia-                                       [4,3-a][1,5]benzodia-                                                                             zepin-5-one                                                 zepin-5-one                                                              207.  1-ethyl-8-nitro-6-(p-                                                                             1-ethyl-8-nitro-4H-s-                                       methoxybenzyl)-4H-s-                                                                              triazolo[4,3-a][1,5]-                                       triazolo[4,3-a][1,5]-                                                                             benzodiazepin-5-one                                         benzodiazepin-5-one                                                      208.  1-cyclopropyl-8-nitro-                                                                            1-cyclopropyl-8-nitro-                                      6-(p-methoxybenzyl)-                                                                              4H-s-triazolo[4,3-a]-                                       4H-s-triazolo[4,3-a]-                                                                             [1,5]benzodiazepin-                                         [1,5]benzodiazepin-                                                                               5-one                                                       5-one                                                                    209.  1-[(dimethylamino)-                                                                               1-[(dimethylamino)-                                         methyl]-8-nitro-6-(p-                                                                             methyl]-8-nitro-4H-s-                                       methoxybenzyl)-4H-s-                                                                              triazolo[4,3-a][1,5]-                                       triazolo[4,3-a][1,5]-                                                                             benzodiazepin-5-one                                         benzodiazepin-5-one                                                      210.  1-methyl-8-chloro-6-                                                                              1-methyl-8-chloro-4H-                                       (p-methoxybenzyl)-4H-                                                                             s-triazolo[4,3-a][1,5]-                                     s-triazolo[4,3-a] [1,5]-                                                                          benzodiazepin-5-one                                         benzodiazepin-5-one                                                      211.  1-methyl-8-nitro-6-                                                                               1-methyl-8-nitro-4H-                                        (p-methoxybenzyl)-4H-                                                                             s-triazolo[4,3-a][1,5]-                                     s-triazolo[4,3-a][1,5]-                                                                           benzodiazepin-5-one                                         benzodiazepin-5-one                                                      212.  1-methyl-8-methoxy-6-                                                                             1-methyl-8-methoxy-                                         (p-methoxybenzyl)-4H-                                                                             4H-s-triazolo[4,3-a]-                                       s-triazolo[4,3-a][1,5]-                                                                           [1,5]benzodiazepin-5-                                       benzodiazepin-5-one                                                                               one                                                   213.  1-methyl-8-methyl-6-                                                                              1-methyl-8-methyl-                                          (p-methoxybenzyl)-4H-                                                                             4H-s-triazolo[4,3-a]-                                       s-triazolo[4,3-a][1,5]-                                                                           [1,5]benzodiazepin-5-                                       benzodiazepin-5-one                                                                               one                                                   214.  1-methyl-8-(trifluoro-                                                                            1-methyl-8-(trifluoro-                                      methyl)-6-(p-methoxy-                                                                             methyl)-4H-s-triazolo-                                      benzyl)-4H-s-triazolo-                                                                            [4,3-a][1,5]benzodia-                                       [4,3-a][1,5]benzodia-                                                                             zepin-5-one                                                 zepin-5-one                                                              215.  1-methyl-8-(trifluoro-                                                                            1-methyl-8-(trifluoro-                                      methyl)-6-(o,p-dimethoxy-                                                                         methyl)-4H-s-triazolo-                                      benzyl)-4H-s-triazolo-                                                                            [4,3-a][1,5]benzodia-                                       [4,3-a][1,5]benzodia-                                                                             zepin-5-one                                                 zepin-5-one                                                              ______________________________________                                    

EXAMPLES 216 - 235

Following the procedure of Example 29, Methods C or I, but substituting the compounds indicated in Column I below for 1-methyl-8-chloro-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in Example 29, Methods C or I, the compounds indicated in Column II are obtained.

    ______________________________________                                                I              II                                                       ______________________________________                                         216.    1-methyl-4H-s-triazolo-                                                                         1-methyl-6-phenyl-4H-                                         [4,3-a][1,5]benzodia-                                                                           s-triazolo[4,3-a][1,5]-                                       zepin-5-one      benzodiazepin-5-one                                   217.    1-methyl-8-chloro-4H-                                                                           1-methyl-8-chloro-6-                                          s-triazolo[4,3-a][1,5]-                                                                         phenyl-4H-s-triazolo-                                         benzodiazepin-5-one                                                                             [4,3-a][1,5]benzodiaze-                                                        pin-5-one                                             218.    1-methyl-8-methoxy-4H-                                                                          1-methyl-8-methoxy-6-                                         s-triazolo[4,3-a][1,5]-                                                                         phenyl-4H-s-triazolo-                                         benzodiazepin-5-one                                                                             [4,3-a][1,5]benzodia-                                                          zepin-5-one                                           219.    1-methyl-8-(trifluoro-                                                                          1-methyl-8-(trifluoro-                                        methyl)-4H-s-triazolo-                                                                          methyl)-6-phenyl-4H-                                          [4,3-a][1,5]benzodia-                                                                           s-triazolo[4,3-a][1,5]-                                       zepin-5-one      benzodiazepin-5-one                                   220.    1-methyl-8-nitro-4H-                                                                            1-methyl-8-nitro-6-                                           s-triazolo[4,3-a][1,5]-                                                                         phenyl-4H-s-triazolo-                                         benzodiazepin-5-one                                                                             [4,3-a][1,5]benzodia-                                                          zepin-5-one                                           221.    1-methyl-9-chloro-                                                                              1-methyl-9-chloro-6-                                          4H-s-triazolo[4,3-a]-                                                                           phenyl-4H-s-triazolo-                                         [1,5]benzodiazepin-5-                                                                           [4,3-a][1,5]benzodia-                                         one              zepin-5-one                                           222.    1-methyl-9-(trifluoro-                                                                          1-methyl-9-(trifluoro-                                        methyl)-4H-s-triazolo-                                                                          methyl)-6-phenyl-4H-                                          [4,3-a][1,5]benzodia-                                                                           s-triazolo[4,3-a]-                                            zepin-5-one      [1,5]benzodiazepin-                                                            5-one                                                 223.    1,8-dimethyl-4H-s-                                                                              1,8-dimethyl-6-phenyl-                                        triazolo[4,3-a][1,5]-                                                                           4H-s-triazolo[4,3-a]-                                         benzodiazepin-5-one                                                                             [1,5]benzodiazepin-                                                            5-one                                                 224.    8-(trifluoromethyl)-4H-                                                                         8-(trifluoromethyl)-6-                                        s-triazolo[4,3-a][1,5]-                                                                         phenyl-4H-s-triazolo-                                         benzodiazepin-5-one                                                                             [4,3-a][1,5]benzodia-                                                          zepin-5-one                                           225.    1-ethyl-8-(trifluoro-                                                                           1-ethyl-8-(trifluoro-                                         methyl)-4H-s-triazolo-                                                                          methyl)-6-phenyl-4H-                                          [4,3-a][ 1,5]benzodia-                                                                          s-triazolo[4,3-a][1,5]-                                       zepin-5-one      benzodiazepin-5-one                                   226.    1-cyclopropyl-8-(tri-                                                                           1-cyclopropyl-8-(tri-                                         fluoromethyl)-4H-s-                                                                             fluoromethyl)-6-phenyl-                                       triazolo[4,3-a][1,5]-                                                                           4H-s-triazolo[4,3-a]-                                         benzodiazepin-5-one                                                                             [1,5]benzodiazepin-                                                            5-one                                                 227.    1-[(dimethylamino)-                                                                             1-[(dimethylamino)-                                           methyl]-8-(trifluoro-                                                                           methyl]-8-(trifluoro-                                         methyl)-4H-s-triazolo-                                                                          methyl)-6-phenyl-4H-                                          [4,3-a][1,5]benzo-                                                                              s-triazolo[4,3-a][1,5]-                                       diazepin-5-one   benzodiazepin-5-one                                   228.    8-nitro-4H-s-triazolo-                                                                          8-nitro-6-phenyl-4H-                                          [4,3-a][1,5]benzodia-                                                                           s-triazolo[4,3-a]-                                            zepin-5-one      [1,5]benzodiazepin-                                                            5-one                                                 229.    1-ethyl-8-nitro-4H-                                                                             1-ethyl-8-nitro-6-                                            s-triazolo[4,3-a]-                                                                              phenyl-4H-s-triazolo-                                         [1,5]benzodiazepin-                                                                             [4,3-a][1,5]benzodia-                                         5-one            zepin-5-one                                           230.    1-cyclopropyl-8-nitro-                                                                          1-cyclopropyl-8-nitro-                                        4H-s-triazolo[4,3-a]-                                                                           6-phenyl-4H-s-triazolo-                                       [1,5]benzodiazepin-5-                                                                           [4,3-a][1,5]benzodia-                                         one              zepin-5-one                                           231.    1-[(dimethylamino)-                                                                             1-[(dimethylamino)-                                           methyl]-8-nitro-4H-                                                                             methyl]-8-nitro-6-                                            s-triazolo[4,3-a]-                                                                              phenyl-4H-s-triazolo-                                         [1,5]benzodiazepin-                                                                             [4,3-a][1,5]benzodia-                                         5-one            zepin-5-one                                           232.    8-chloro-4H-s-tria-                                                                             8-chloro-6-phenyl-4H-                                         zolo[4,3-a][1,5]-                                                                               s-triazolo[4,3-a]-                                            benzodiazepin-5-one                                                                             [1,5]benzodiazepin-5-                                                          one                                                   233.    1-ethyl-8-chloro-4H-                                                                            1-ethyl-8-chloro-6-                                           s-triazolo[4,3-a]-                                                                              phenyl-4H-s-triazolo-                                         [1,5]benzodiazepin-                                                                             [4,3-a][1,5]benzodia-                                         5-one            zepin-5-one                                           234.    1-cyclopropyl-8- 1-cyclopropyl-8-chloro-                                       chloro-4H-s-triazolo-                                                                           6-phenyl-4H-s-triazolo-                                       [4,3-a][1,5]benzodia-                                                                           [ 4,3-a][1,5]benzodia-                                        zepin-5-one      zepin-5-one                                           235.    1-[(dimethylamino)-                                                                             1-[(dimethylamino)-                                           methyl]-8-chloro-4H-                                                                            methyl]-8-chloro-6-                                           s-triazolo[4,3-a]-                                                                              phenyl-4H-s-triazolo-                                         [1,5]benzodiazepin-                                                                             [4,3-a][1,5]benzodia-                                         5-one            zepin-5-one                                           ______________________________________                                    

EXAMPLE 236 1-Methyl-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,5-]benzodiazepin-5-one

To a stirred mixture of 12.4 g of 1-methyl-8-chloro-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one, 5 g of copper powder and 1 g of cupric sulfate in 100 ml of o-chlorobromobenzene at 90° C, was added, portionwise over a 30 minute period, 4.5 g of potassium acetate. The reaction is heated at 165° C for 9 hours and then worked up as described in Example 29, Method C, to give the title compound.

EXAMPLES 237 - 243

Following the procedure of Example 236 but substituting the compounds indicated in Column I below for 1-methyl-8-chloro-4H-s-triazolo[4,3-a][1,5]benzodiazepin5-one in Example 236, the compounds indicated in Column II are obtained.

    ______________________________________                                         I                   II                                                         ______________________________________                                         237. 1-methyl-4H-s-triazolo-                                                                          1-methyl-6-(o-chloro-                                        [4,3-a][1,5]benzodia-                                                                            phenyl)-4H-s-triazolo-                                       zepin-5-one       [4,3-a][1,5]benzodia-                                                          zepin-5-one                                             238. 1-methyl-8-chloro-4H-                                                                            1-methyl-8-chloro-6-                                         s-triazolo[4,3-a][1,5]-                                                                          (o-chlorophenyl)-4H-                                         benzodiazepin-5-one                                                                              s-triazolo[4,3-a][1,5]-                                                        benzodiazepin-5-one                                     239. 1-methyl-8-methoxy-4H-                                                                           1-methyl-8-methoxy-6-                                        s-triazolo[4,3-a][1,5]-                                                                          (o-chlorophenyl)-4H-s-                                       benzodiazepin-5-one                                                                              triazolo[4,3-a][1,5]-                                                          benzodiazepin-5-one                                     240. 1-methyl-8-(trifluoro-                                                                           1-methyl-8-(trifluoro-                                       methyl)-4H-s-triazolo-                                                                           methyl)-6-(o-chloro-                                         [4,3-a][1,5]benzodia-                                                                            phenyl)-4H-s-triazolo-                                       zepin-5-one       [4,3-a][1,5]benzodia-                                                          zepin-5-one                                             241. 1-methyl-8-nitro-4H-                                                                             1-methyl-8-nitro-6-                                          s-triazolo[4,3-a]-                                                                               (o-chlorophenyl)-4H-                                         [1,5]benzodiazepin-                                                                              s-triazolo[4,3-a]-                                           5-one             [1,5]benzodiazepin-5-                                                          one                                                     242. 1-methyl-9-chloro-4H-                                                                            1-methyl-9-chloro-6-                                         s-triazolo[4,3-a]-                                                                               (o-chlorophenyl)-4H-s-                                       [1,5]benzodiazepin-                                                                              triazolo[4,3-a][1,5]-                                        5-one             benzodiazepin-5-one                                     243. 1-methyl-9-(trifluoro-                                                                           1-methyl-9-(trifluoro-                                       methyl)-4H-s-triazolo-                                                                           methyl)-6-(o-chloro-                                         [4,3-a][1,5]benzodia-                                                                            phenyl)-4H-s-triazolo-                                       zepin-5-one       [4,3-a][1,5]benzodia-                                                          zepin-5-one                                             244. 1,8-dimethyl-4H-s-                                                                               1,8-dimethyl-6-(o-chloro-                                    triazolo[4,3-a][1,5]-                                                                            phenyl)-4H-s-triazolo-                                       benzodiazepin-5-one                                                                              [4,3-a][1,5]benzodiaze-                                                        pin-5-one                                               ______________________________________                                    

EXAMPLE 245 N-Benzyl-N-(2'-nitro-5'-chlorophenyl)malonamic acid, ethyl ester

52 g of N-benzyl-N-(2-nitro-5-chlorophenyl) amine and 35.5 g of (chloroformyl)acetic acid ethyl ester in 500 ml benzene are refluxed for 15 hours. The reaction is cooled, washed with dilute aqueous sodium bicarbonate, dried and the solvent evaporated to give the title compound.

EXAMPLES 246 - 252

Following the procedure of Example 245, but substituting the compounds indicated in Column I below for N-benzyl-N-(2-nitro-5-chlorophenyl)amine in Example 245, the compounds indicated in Column II are obtained.

    ______________________________________                                         I                  II                                                          ______________________________________                                         246.  N-benzyl-N-[2-nitro-                                                                           N-benzyl-N-[2'-nitro-5'-                                       5-(trifluoromethyl)-                                                                           (trifluoromethyl)phenyl]-                                      phenyl amine    malonamic acid ethyl                                                           ester                                                    247.  N-benzyl-N-(2-nitro-                                                                           N-benzyl-N-(2'-nitro-                                          5-methylphenyl)amine                                                                           5'-methylphenyl)malona-                                                        mic acid ethyl ester                                     248.  N-benzyl-N-(2-nitro-                                                                           N-benzyl-N-(2'-nitro-                                          5-methoxyphenyl)amine                                                                          5'-methoxyphenyl)malona-                                                       mic acid ethyl ester                                     249.  N-benzyl-N-(2-nitro-                                                                           N-benzyl-N-(2'-nitro-                                          phenyl)amine    phenyl)malonamic acid                                                          ethyl ester                                              250.  N-benzyl-N-(2-nitro-                                                                           N-benzyl-N-(2'-nitro-                                          4-chlorophenyl)amine                                                                           4'-chlorophenyl)                                                               malonamic acid, ethyl                                                          ester                                                    251.  N-(4-methoxybenzyl)-                                                                           N-(4-methoxybenzyl)-                                           N-(2-nitro-5-chloro-                                                                           N-(2'-nitro-5'-chloro-                                         phenyl)amine    phenyl)malonamic acid                                                          ethyl ester                                              252.  N-(4-methoxybenzyl)-                                                                           N-(4-methoxybenzyl)-                                           N-[2-nitro-5-(trifluoro-                                                                       N-[2'-nitro-5'-(tri-                                           methyl)phenyl]amine                                                                            fluoromethyl)phenyl]-                                                          malonamic acid, ethyl                                                          ester                                                    ______________________________________                                    

EXAMPLES 253 - 256

Following the procedure of Example 245 but substituting the compounds indicated in column I below for (chloroformyl)acetic acid ethyl ester in example 245, the compounds indicated in column II are obtained.

    ______________________________________                                         I                   II                                                         ______________________________________                                         253.  (chloroformyl)acetic                                                                            N-benzyl-N-(2'-nitro-5'-                                      acid methyl ester                                                                               chlorophenyl)malonamic                                                         acid methyl ester                                       254.  (chloroformyl)acetic                                                                            N-benzyl-N-(2'-nitro-5'-                                      acid butyl ester chlorophenyl)malonamic                                                         acid butyl ester                                        255.  (chloroformyl)acetic                                                                            N-benzyl-N-(2'-nitro-5'-                                      acid phenyl ester                                                                               chlorophenyl)malonamic                                                         acid phenyl ester                                       256.  (chloroformyl)acetic                                                                            N-benzyl-N-(2'-nitro-5'-                                      acid (p-methylphenyl)                                                                           chlorophenyl)malonamic                                        ester            acid (p-methylphenyl)-                                                         ester                                                   ______________________________________                                    

EXAMPLE 257 N-Benzyl-N-(2'-amino-5'-chlorophenyl)malonamic acid ethyl ester Method A

37.6 g of N-benzyl-N-(2'-nitro-5'-chlorophenyl)malonamic acid ethyl ester and 0.5 g of 10% palladium-on-carbon in 200 ml ethanol containing 0.2 moles of hydrogen chloride are hydrogenated on a Parr shaker, with cooling, at ambient temperature. The reaction is stopped after 0.3 moles of hydrogen are absorbed or when hydrogen uptake ceases, whichever comes first. The reaction is diluted with chloroform, filtered and the filtrate evaporated. The residue is suspended in methylene chloride and shaken with excess aqueous sodium bicarbonate. The organic phase is washed with water, dried and evaporated to give the title compound.

Method B

Following the procedure of Example 257, Method A, but substituting Raney nickel and methanol for the 10% palladium-on-carbon and ethanolic hydrogen chloride, respectively, in Example 257, Method A, and running the reaction at an initial hydrogen pressure of 3 atm., gives the title compound.

EXAMPLES 258 - 268

Following the procedure of Example 257, Methods A and B, but substituting the compounds indicated in Column I below for N-benzyl-N-(2'-nitro-5'-chlorophenyl)malonamic acid ethyl ester in Example 257, Methods A and B, the compounds indicated in Column II are obtained.

    ______________________________________                                             I                   II                                                     ______________________________________                                         258. N-benzyl-N-[2'-nitro-                                                                             N-benzyl-N-[2'-amino-5'-                                    5'-(trifluoromethyl)phenyl]                                                                       (trifluoromethyl)phenyl]                                    malonamic acid ethyl ester                                                                        malonamic acid ethyl                                                           ester                                                  259. N-benzyl-N-(2'-nitro-                                                                             N-benzyl-N-(2'-amino-                                       5'-methylphenyl)   5'-methylphenyl)malona-                                     malonamic acid ethyl                                                                              mic acid ethyl ester                                        ester                                                                     260. N-benzyl-N-(2'-nitro-                                                                             N-benzyl-N-(2'-amino-                                       5'-methoxyphenyl)  5'-methoxyphenyl)                                           malonamic acid ethyl                                                                              malonamic acid ethyl                                        ester              ester                                                  261. N-benzyl-N-(2'-nitro-                                                                             N-benzyl-N-(2'-amino-                                       phenyl)malonamic acid,                                                                            phenyl)malonamic                                            ethyl ester        acid, ethyl ester                                      262. N-benzyl-N-(2'-nitro-                                                                             N-benzyl-N-(2'-amino-                                       4'-chlorophenyl)   4'-chlorophenyl)                                            malonamic acid, ethyl                                                                             malonamic acid, ethyl                                       ester              ester                                                  263. N-(4'-matyoxybenzyl)-                                                                             N(4-methoxybenzyl)-                                         N-(2'-nitro-5'-chloro-                                                                            N-(2'-amino-5'-chloro-                                      phenyl)malonamic acid                                                                             phenyl)malonamic acid                                       ethyl ester        ethyl ester                                            264. N-(4-methoxybenzyl)-N-                                                                            N-(4-methoxybenzyl)-N-                                      [2'-nitro-5'-(trifluoro-                                                                          [2'-amino-5'-(trifluoro-                                    methyl)phenyl]malonamic                                                                           methyl)phenyl]malonamic                                     acid, ethyl ester  acid, ethyl ester                                      265. N-benzyl-N-(2'-nitro-                                                                             N-benzyl-N-(2'-amino-                                       5'-chlorophenyl)malona-                                                                           5'-chlorophenyl)malonamic                                   mic acid methyl ester                                                                             acid methyl ester                                      266. N-benzyl-N-(2'-nitro-                                                                             N-benzyl-N-(2'-amino-                                       5'-chlorophenyl)malona-                                                                           5'-chlorophenyl)malona-                                     mic acid butyl ester                                                                              mic acid butyl ester                                   267. N-benzyl-N-(2'-nitro-                                                                             N-benzyl-N-(2'-amino-                                       5'-chlorophenyl)malona-                                                                           5'-chlorophenyl)malonamic                                   mic acid phenyl ester                                                                             acid phenyl ester                                      268. N-benzyl-N-(2'-nitro-                                                                             N-benzyl-N-(2'amino-                                        5'-chlorophenyl)malona-                                                                           5'-chlorophenyl)malona-                                     mic acid (p-methyl-                                                                               mic acid (p-methylphenyl)                                   phenyl)ester       ester                                                  ______________________________________                                    

EXAMPLES 269 - 279

Following the procedure of Example 140, Methods B and D, but substituting the compounds indicated in Column I below for N-benzyl-N-(2'-amino-5'-chlorophenyl)malonamic acid, ethyl ester in Example 140, Methods B and D, the compounds indicated in Column II are obtained.

    ______________________________________                                         269. N-benzyl-N-[2'-amino-                                                                             7-(trifluoromethyl)-5-                                      5'-(trifluoromethyl)-                                                                             benzyl-1H-1,5-benzodia-                                     phenyl]malonamic   zepine-2,4-dione                                            acid ethyl ester                                                          270. N-benzyl-N-(2'-amino-                                                                             7-methyl-5-benzyl-1H-                                       5'-methylphenyl)   1,5-benzodiazepine-                                         malonamic acid     2,4-dione                                                   ethyl ester                                                               271. N-benzyl-N-(2'-amino-                                                                             7-methoxy-5-benzyl-1H-                                      5'-methoxyphenyl)  1,5-benzodiazepine-                                         malonamic acid     2,4-dione                                                   ethyl ester                                                               272. N-benzyl-N-(2'-amino-                                                                             5-benzyl-1H-1,5-benzodia-                                   phenyl)malonamic   zepine-2,4-dione                                            acid ethyl ester                                                          273. N-benzyl-N-(2'-amino-                                                                             8-chloro-5-benzyl-1H-                                  4'-chlorophenyl)malona-                                                             1,5-benzodiazepine-2,4-                                                        mic acid, ethyl ester                                                                             dione                                                  274. N-(4-methoxybenzyl)-                                                                              7-chloro-5-(p-methoxy-                                      N-(2'-amino-5'-chloro-                                                                            benzyl-1H-1,5-benzodia-                                     phenyl)malonamic acid                                                                             zepine-2,4-dione                                            ethyl ester                                                               275. N-(4-methoxybenzyl)-N-                                                                            7-(trifluoromethyl)-5-                                      [2'-amino-5'-(trifluoro-                                                                          (p-methoxybenzyl)-1H-                                       methyl)phenyl]malonamic                                                                           1,5-benzodiazepine-2,4-                                     acid, ethyl ester  dione                                                  276. N-benzyl-N-(2'-amino-                                                                             7-chloro-5-benzyl-1H-                                  5'-chlorophenyl)malona-                                                             1,5-benzodiazepine-2,4-                                                        mic acid methyl ester                                                                             dione                                                  277. N-benzyl-N-(2'-amino-                                                                             7-chloro-5-benzyl-1H-                                       5'-chlorophenyl)malona-                                                                           1,5-benzodiazepine-2,4-                                     mic acid butyl ester                                                                              dione                                                  278. N-benzyl-N-(2'-amino-                                                                             7-chloro-5-benzyl-1H-                                       5'-chlorophenyl)malona-                                                                           1,5-benzodiazepine-2,4-                                     mic acid phenyl ester                                                                             dione                                                  279. N-benzyl-N-(2'-amino-                                                                             7-chloro-5-benzyl-1H-                                       5'-chlorophenyl)malona-                                                                           1,5-benzodiazepine-2,4-                                     mic acid (p-methyl-                                                                               dione                                                       phenyl)ester                                                              ______________________________________                                    

EXAMPLE 280 2,7-Dichloro-5-phenyl-3H-1,5-benzodiazepin-4-one Method A

28.6 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione and 20.8 g of phosphorus pentachloride in 1000 ml of benzene is stirred for 10 hours, then refluxed for 3 hours. The reaction is evaporated, azeotroped with benzene and the solvent evaporated. The residue is stirred with carbon tetrachloride and the title compound filtered off and dried.

Method B

To 28.6 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione and 24.2 g of dimethylaniline in 200 ml of benzene is added 10.2 g of phosphorous oxychloride. The reaction mixture is refluxed for 14 hours under argon, cooled to 7° C, diluted with 100 ml of cold water and stirred for 0.25 hour. The organic layer is separated, washed with 100 ml of cold water, dried and evaporated. The residue is stirred with 50 ml of carbon tetrachloride and the title compound is filtered off and dried.

EXAMPLE 281 Acetic acid 2-(7-chloro-5-phenyl-3H-1,5-benzodiazepin4-one-2-yl)hydrazide Method A

3.0 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepin4-one-2-thione and 1.8 g of acetic acid hydrazide in 100 ml ethanol is refluxed for 24 hours. During this time a slow stream of nitrogen is bubbled through the reaction mixture. The mixture is evaporated, the residue taken up in methylene chloride, washed with water, dried and the solvent evaporated. The residue is chromatographed on 10-1000μ silica gel plates (20 × 20 cm) with acetone-methanol (9:1) eluant. The band containing the product is removed and stirred with acetone-methanol (4:1). The silica gel is filtered off and the filtrate evaporated to give the title compound.

Method B

3.0 g of 2-hydrazino-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one and 1.4 g of ethyl 1-acetoxyformate in 50 ml tetrahydrofuran containing one drop of N-methylmorpholine is stirred at room temperature for 24 hours. The reaction mixture is evaporated to give the title compound. Further purification is accomplished, if necessary, by chromatography as described in Example 281, Method A.

EXAMPLE 282

2-Hydrazino-7-chloro-5-3H-1,5-benzodiazepin-4-one

Method A

3.8 g of 2-[2(t-butoxycarbonyl)hydroazino]-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one and 1.78 g of hydrogen bromide in 200 ml methylene chloride is stirred for 2 hours. The reaction mixture is washed with aqueous sodium bicarbonate, water, dried and evaporated. The product is stirred with carbon tetrachloride and the title compound is filtered off and dried.

Method B

4.32 g of 2-[2-(benzyloxycarbonyl)hydrazino]-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one in 400 ml 1,2-dimethoxy-ethane containing 0.4 g of 10% palladium-on-carbon is hydrogenated at 40 p.s.i. hydrogen pressure until 0.01 moles of hydrogen are absorbed. The reaction is filtered, the filtrate evaporated at room temperature and the residue stirred with carbon tetrachloride to give the title compound.

EXAMPLE 283 2-[2-(t-butoxycarbonyl)hydrazino]-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one

3.16 g of 2-(methylthio)-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one and 1.41 g of t-butylcarbazate in 60 ml of dimethyl formamide are refluxed for 20 hours while a slow stream of nitrogen is bubbled through the reaction. The reaction is worked up as described in Example 29, Method A, to give the title compound.

EXAMPLE 284

2-[2-(Benzyloxycarbonyl)hydrazino]-7-chloro-5-phenyl-3-H-1,5-benzodiazepin-4-one

Following the procedure of Example 283, but substituting benzylcarbazate for t-butylcarbazate in Example 283, the title compound is obtained.

EXAMPLE 285 7-Amino-5-phenyl-1H-1,5-benzodiazepine-2,4-dione

29.7 g of 7-nitro-5-phenyl-1-H-1,5-benzodiazepine-2,4-dione in 200 ml ethanol containing 1.0 g of Raney nickel is hydrogenated at room temperature at an initial hydrogen pressure of 50 p.s.i. The reaction is stopped after 0.3 moles of hydrogen has been absorbed. The reaction mixture is filtered and the filtrate evaporated to give 7-amino-5-phenyl-3H-1,5-benzodiazepine-2,4-dione.

EXAMPLE 286 7-Diazonium-5-phenyl-1H-1,5-benzodiazepin-4-one, sulfate

20 g of 7-amino-5-phenyl-1H-1,5-benzodiazepine-2,4-dione in 100 ml of acetic acid is added to a solution of 7.62 g of nitrosysulfuric acid in 10 ml of acetic at 0° C. After 30 minutes, 100 ml of ether is added, with stirring and cooling, and the precipitated diazonium sulfate is filtered off and dried.

EXAMPLE 287 7-(Methylthio)-5-phenyl-1H-1,5-benzodiazepine-2,4-dione

3.76 g of 7-diazonium-5-phenyl-1H-1,5-benzodiazepine-2,4-dione sulfate is added portionwise with stirring under a dry-ice condenser, to a solution of 2.58 g of potassium methyl mercaptide in 100 ml of methyl mercaptan. The reaction is gently refluxed for 24 hours. The reaction is evaporated; the residue diluted with 200 ml of methylene chloride, washed with a solution of 1.35 g acetic acid in 100 ml water, dried and evaporated to give the title compound. The product may be further purified by chromatography on silica gel (e.g. 200-1000μ, 20 × 20 cm plates) using chloroform-ethyl acetate (6:4) as eluting solvent. The band containing the title compound is removed, stirred with EtOAc-MeOH (9:1) and the silica gel is filtered off. The filtrate is evaporated to give the title compound.

EXAMPLE 288 1-Methyl-8-(methylsulfinyl)-6-phenyl-4H-s-triazolo-[4,3-a][1,5]benzodiazepin-5-one

3.36 g of 1-methyl-8-(methylthio)-6-phenyl-4-H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one and 2.14 g of sodium metaperiodate in 500 ml methanol is stirred at +5° C for 24 hours. The reaction is evaporated; the residue dissolved in methylene chloride, washed with water, dried and concentrated. The concentrate is chromatographed on silica gel (20-1000μ plates, 20 × 20 cm) using acetone-methanol (9:1) as eluting solvent. The band containing the product is removed, stirred with acetone-methanol (4:1) and the silica gel filtered off. The filtrate is evaporated to give the title compound.

EXAMPLE 289 1-Methyl-8-amino-6-phenyl-4H-s-triazolo[4,3-a][1,5]-benzodiazepin-5-one

33.5 g of 1-methyl-8-nitro-6-phenyl-4H-s-triazolo[4,3-a][1,5] benzodiazepin-5-one in 100 ml of ethanol containing 2.0 g of Raney nickel is hydrogenated at room temperature at an initial hydrogen pressure of 50 p.s.i. The reaction is stopped when 0.3 moles of hydrogen has been absorbed; the suspension is filtered and the filtrate evaporated to give the title compound.

EXAMPLE 290 1-Methyl-8-acetamido-6-phenyl-4-H-s-triazolo[4,3-a][1,5]-benzodiazepin-5-on

3.47 g of 1-methyl-8-amino-6-phenyl-4-H-s-triazolo-[4,3-a][1,5]benzodiazepin-5-one and 1.02 g of acetic anhydride in 50 ml pyridine is stirred for 12 hours then refluxed for 30 minutes. The reaction is evaporated; the residue is taken up in chloroform, washed with dilute aqueous sodium bicarbonate, with water and dried. The solvent is evaporated to give the title compound.

EXAMPLE 291 4-Hydroxyl-1-methyl-8-chloro-6-phenyl-4H-s-triazolo-[4,3-a][1,5]benzodiazepin-5-one

44.6 g of 4-(benzyloxy)-1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 400 ml of ethanol containing 2.0 g of Raney nickel is hydrogenated at an initial hydrogen pressure of 40 p.s.i. After 0.1 mole of hydrogen has been absorbed, the reaction is stopped, filtered and the solvent evaporated. The residue is triturated in ether and the title compound filtered off and dried.

EXAMPLES 292 - 296

Following the procedure of Example 124, but substituting the compounds indicated in column I below for diethylamine in example 124, the compounds in column II are obtained.

    ______________________________________                                             I               II                                                         ______________________________________                                         292. 4-phenylpiperdine                                                                             1-(4-phenylpiperdinomethyl)-                                                   8-chloro-6-phenyl-4H-s-triazolo-                                               [4,3-a][1,5]benzodiazepin-5-one                            293. N-methylpiperazine                                                                            1-(4-methylpiperazinomethyl)-                                                  8-chloro-6-phenyl-4H-s-trazolo                                                 [4,3-a][1,5]benzodiazepin-5-one                            294. N-(methoxyphenyl)-                                                                            1-[4-(2-methoxyphenyl)piperazino-                               piperazine     methyl]-8-chloro-6-phenyl-4H-                                                  s-trazolo[4,3-a][1,5]benzodiazepin-                                            5-one                                                      295. silver nitrite 1-(nitromethyl)-8-chloro-6-phenyl-                                             4H-s-triazolo[4,3-a][1,5]benzo-                                                diazepin-5-one                                             296. N-(t-butoxycarbonyl)-                                                                         1-[4-(t-butoxycarbonyl)-                                        piperazine     piperazinomethyl]-8-chloro-6-                                                  phenyl-4H-s-triazolo[4,3-a][1,5]-                                              benzodiazepin-5-one                                        ______________________________________                                    

EXAMPLE 297 1-Piperazinomethyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]-benzodiazepin-5-one

2 g. of 1-[4-(t-butoxycarbonyl)-piperazinomethyl]-8-chloro-6-phenyl-4-H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 50 ml of trifluoroacetic acid is stirred for 2 hours. The reaction mixture is evaporated and the residue partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is washed with water, dried and evaporated to give the title compound.

EXAMPLE 298 4-(3,4,5-trimethoxybenzoyloxy)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one

Following the procedure of example 281, method B, but substituting ethyl 1-(3,4,5-trimethoxybenzoyloxy)formate for ethyl 1-acetoxyformate and 4-hydroxy-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one for 2-hydrazino-7chloro-5 -phenyl-3H-1,5-benzodiazepin-4-one in example 281, method B, the title compound is obtained.

EXAMPLE 299 1-Methyl-8-chloro-6-(2',4'-dichlorophenyl)-4H-s-triazolo-[4,3-a][1,5]benzodiazepin-5-one Part A

20 g of 2',4',5-trichloro-2-nitrodiphenylamine in 100 ml of methanol containing 0.2 g of Raney nickel is hydrogenated at an initial hydrogen pressure of 7 atm. until three molar equivalents of hydrogen is consumed. The suspension is filtered and the filtrate evaporated to give 2',4',5-trichloro-2-aminodiphenylamine.

Part B

Following the procedure of example 140, method A, but substituting the above produced 2',4',5-trichloro-2-aminodiphenylamine for 2-benzylamino-4-chloro-aniline in example 140, method A, gives 7-chloro-(2',4'-dichlorophenyl)-1H-1,5-benzodiazepin-2,4-dione.

Part C

Following the procedure of example 1 but substituting the above produced 7-chloro-5-(2',4'-dichlorophenyl)-1H-1,5-benzodiazepin-2,4-dione for 7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione in example 1, gives 7-chloro-5-(2',4'-dichlorophenyl)-1H-1,5-benzodiazepin-4-one-2-thione.

Part D

Following the procedure of example 29, method A, but substituting the above produced 7-chloro-5-(2',4'-dichlorophenyl)-1H-1,5-benzodiazepin-4-one-2-thione for 7-chloro-5phenyl -1-H-1,5-benzodiazepin-4-one-2-thione in example 29, method A, gives the title compound of formula 1.

EXAMPLES 300 - 318

Following the procedure of parts A to D of the foregoing example but employing as starting materials the substituted compound of formula 15 where m is zero wherein the substituents and the position they occupy are indicated below:

    __________________________________________________________________________     Example                                                                        No.  3   4    5   6   2'   3'                                                                               4'   5'  6'                                       __________________________________________________________________________     300.     Cl   Cl                                                               301. Cl                                                                        302.     Cl                  CH.sub.3 SO.sub.2                                 303.     CF.sub.3     Cl          CF.sub.3                                     304.          Cl      CH.sub.3                                                                              CH.sub.3                                          305.          Cl      CH.sub.3                                                                              Cl                                                306.          CH.sub.2 S     Cl                                                307.          Cl      Cl     CH.sub.3                                          308.     Cl       Cl                                                           309.     CH.sub.3 O                                                                          CH.sub.3 O                                                       310.     Cl   Cl           Cl                                                  311.     Cl           OCH.sub.3   OCH.sub.3                                    312.              Cl                                                           313.                  Cl   Cl                                                  314. CH.sub.3 O   CH.sub.3 O                                                   315.     Cl   CH.sub.3                                                         316.     CH.sub.3 SO.sub.2                                                     317.     Cl           CH.sub.3 S                                               318.     Cl           CH.sub.3 SO.sub.2                                        319.          Cl      F               F                                        __________________________________________________________________________

there is obtained the correspondingly substituted compound of formula I wherein the substitutents and the position they occupy are indicated below:

    __________________________________________________________________________     Example                                                                        No.  7   8   9    10  2'   3' 4'   5'  6'                                      __________________________________________________________________________     300.     Cl  Cl                                                                301.              Cl                                                           302.         Cl               CH.sub.3 SO.sub.2                                303.         CF.sub.3 Cl           CF.sub.3                                    304.     Cl           CH.sub.3                                                                               CH.sub.3                                         305.     Cl           CH.sub.3                                                                               Cl                                               306.     CH.sub.3 S           Cl                                               307.     Cl           Cl      CH.sub.3                                         308. Cl      Cl                                                                309.     CH.sub.3 O                                                                         CH.sub.3 O                                                        310.     Cl  Cl               Cl                                               311.         Cl       OCH.sub.3    OCH.sub.3                                   312. Cl                                                                        313.                  Cl   Cl                                                  314. OCH.sub.3    OCH.sub.3                                                    315.     CH.sub.3                                                                           Cl                                                                316.         CH.sub.3 SO.sub.2                                                 317.         Cl       SCH.sub.3                                                318.         Cl       CH.sub.3 SO.sub.2                                        319.     CL           F                F                                       __________________________________________________________________________

EXAMPLE 320 1-Methyl-8-(methylsulfonyl)-6-phenyl-4H-s-triazolo-[4,3-a][1,5]benzodiazepin-5-one

Following the procedure of example 288, but using 4.14 g instead of 2.14 g of sodium metaperiodate, the title compound is obtained.

EXAMPLE 321 4-Chloro-2',6'-difluoro-2-nitrophenylamine

19.1 g of 2,4-dichloronitrobenzene and 126.0 g of 2,6-difluoroaniline and 16.4 g of sodium acetate are refluxed for 24 hours. After cooling, the reaction is poured into excess dilute hydrochloric acid, extracted with ether and the ether is then dried and evaporated. The residue from the ether phase is chromatographed on neutral alumina with hexane-ether (9:1). The eluant is evaporated. The title compound is purified by recrystallization from ethanol.

EXAMPLE 322 1-Methyl-8-chloro-6-(5'-chloro-2'-nitrophenyl)-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one

Following the procedure of parts B through D of example 299, but substituting 2-amino-5'-chloro-2'-nitrodiphenylamine for 2',4',5-trichloro-2-aminodiphenyl-amine in part B, the title compound is obtained.

EXAMPLE 323 1-Ethoxymethyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepin-5-one

Following the procedure of example 124, but substituting sodium ethoxide and ethanol for diethylamine in example 124, the title compound is obtained.

EXAMPLE 324 4-(2-Dimethylaminoethyl)-1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a] [1,5]benzodiazepin-5-one

37.0 g of 1-methyl-8-chloro-6-phenyl-4H-s-triazolo-[4,3-a][1,5]benzodiazepin-5-one and 7.8 g of a 50 percent sodium hydride mineral oil dispersion in 400 ml of dry 1,2-dimethoxyethane are stirred for 2 hours. A solution of 13.7 g of 2-dimethylaminoethyl bromide in 40 ml of dry 1,2-dimethoxyethane is added and the whole is stirred for 18 hours. The solvent is evaporated and the residue is partitioned between methylene chloride and water. The organic phase is washed with water, dried and evaporated to give the title compound.

EXAMPLES 325-338

Following the procedure of example 324 but substituting the compounds indicated in column I below for 2-dimethylaminoethyl bromide in example 324, the compounds indicated in column II are obtained:

    __________________________________________________________________________         I                 II                                                       __________________________________________________________________________     325.                                                                              3-dimethylaminopropyl                                                                         4-(3-dimethylaminopropyl)-1-                                    chloride       methyl-8-chloro-6-phenyl-4H-s-                                                 triazolo[4,3,-a][1,5]benzodia-                                                 zepin-5-one                                                  326.                                                                              2-pyrrolidinoethyl                                                                            4-(2-pyrrolidinoethyl)-1-                                       chloride       methyl-8-chloro-6-phenyl-4H-s-                                                 triazolo[4,3-a][1,5]benzodia-                                                  zepin-5-one                                                  327.                                                                              2-diethylaminoethyl                                                                           4-(2-diethylaminoethyl)-1-                                      bromide        methyl-8-chloro-6-phenyl-4H-s-                                                 triazolo[4,3-a][1,5]benzodia-                                                  zepin-5-one                                                  328.                                                                              2-morpholinoethyl                                                                             4-(2-morpholinoethyl)-1-methyl-                                 chloride       8-chloro-6-phenyl-4H-s-triazolo-                                               [4,3-a][1,5]benzodiazepin-5-                                                   one                                                          329.                                                                              2-piperidinoethyl                                                                             4-(2-piperidinoethyl)-1-                                        chloride       methyl-8-chloro-6-phenyl-4H-s-                                                 triazolo[4,3-a][1,5]benzodia-                                                  zepin-5-one                                                  330.                                                                              2-(4-phenylpiperi-                                                                            4-[2-(4-phenylpiperidino)ethyl]-                                dino)ethyl chloride                                                                           1-methyl-8-chloro-6-phenyl-4H-s-                                               triazolo[4,3-a][1,5]benzodia-                                                  zepin-5-one                                                  331.                                                                              2-piperazinoethyl                                                                             4-(2-piperazinoethyl)-1-methyl-                                 chloride       8-chloro-6-phenyl-4H-s-                                                        triazolo[4,3-a][1,5]benzodia-                                                  zepin-5-one                                                  332.                                                                              2-(4-methylpiperazino)-                                                                       4-[2-(4-methylpiperazino)ethyl]                                 ethyl chloride 1-methyl-8-chloro-6-phenyl-4H-s-                                               triazolo[4,3-a][1,5]benzodia-                                                  zepin-5-one                                                  333.                                                                              2-(4-phenylpiperazino)-                                                                       4-[2-(4-phenylpiperazino)ethyl]                                 ethyl chloride 1-methyl-8-chloro-6-phenyl-4H-s-                                               triazolo[4,3-a][1,5]benzodiazepin-                                             5-one                                                        334.                                                                              3-[4-(2-methoxyphenyl)-                                                                       4-[3-[2-methoxyphenyl)pipera-                                   piperazino]propyl-                                                                            zino]propyl]-1-methyl-8-chloro-                                 chloride       6-phenyl-4H-s-triazolo[4,3-a]-                                                 [1,5]benzodiazepin-5-one                                     335.                                                                              3-piperidinopropyl                                                                            4-(3-piperidinopropyl)-1-methyl-                                chloride       8-chloro-6-phenyl-4H-s-triazolo-                                               [4,3-a][1,5]benzodiazepin-5-one                              336.                                                                              3-methylpipera-                                                                               4-[3-(4-methylpiperazino)propyl]-                               zino)propyl chloride                                                                          1-methyl-8-chloro-6-phenyl-4H-                                                 s-triazolo[4,3-a][1,5]benzodia-                                                zepin-5-one                                                  337.                                                                              2-(N-benzyl-N- 4-[2-(N-benzyl-N-methylamino)ethyl]-                            methylamino)ethyl                                                                             1-methyl-8-chloro-6-phenyl-4H-                                  chloride       s-triazolo[4,3-a][1,5]benzodia-                                                zepin-5-one                                                  338.                                                                              3-[(t-butoxycarbonyl)-                                                                        4-[3-[(t-butoxycarbonyl)amino]-                                 amino]propyl chloride                                                                         propyl]-1-methyl-8-chloro-6-                                                   phenyl-4H-s-triazolo[4,3-a][1,5]-                                              benzodiazepin-5-one                                          __________________________________________________________________________

EXAMPLE 339 4-(2-Methylaminoethyl)-1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one

4 g of 4-[2-(N-benzyl-N-methylamino)ethyl]-1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 100 ml of ethanol containing 0.4 g of Raney nickel is hydrogenated at 50 p.s.i. hydrogen pressure until 0.0085 moles of hydrogen is absorbed. The suspension is filtered and the filtrate is evaporated. The residue is triturated with a small amount of cold ether and the title compound is filtered off and dried.

EXAMPLE 340 4-(3-aminopropyl)-1-methyl-8-chloro-6-phenyl-4H-s-triazolo-[4,3-a][1,5]benzodiazepin-5-one

2.5 g of 4-[2-(N-t-butoxycarbonylamino)propyl]-1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 50 ml of trifluoroacetic acid is stirred at room temperature for 2 hours. The reaction is evaporated and the residue is stirred with a solution of 1.9 g of sodium bicarbonate in 400 ml of methanol-water (10:1). After 3 hours the reaction is evaporated and the residue is partitioned between methylene chloride and water. The methylene chloride is washed with water, dried and evaporated to give the title compound.

EXAMPLES 341-343

Following the procedure of example 29, Method A, but substituting the compounds indicated in column I below for acetic acid hydrazide in example 29, Method A, the compounds indicated in column II are obtained.

    __________________________________________________________________________         I                II                                                        __________________________________________________________________________     341.                                                                              picolinic acid hydrazide                                                                     1-(2-pyridyl)-8-chloro-6-phenyl-                                               4H-s-triazolo[4,3-a][1,5]benzo-                                                diazepin-5-one                                                342.                                                                              nicotinic acid hydrazide                                                                     1-(3-pyridyl)-8-chloro-6-phenyl-                                               4H-s-triazolo[4,3-a][1,5]benzo-                                                diazepin-5-one                                                343.                                                                              isonicotinic acid                                                                            1-(4-pyridyl)-8-chloro-6-phenyl-                                 hydrazide     4H-s-triazolo[4,3-a][1,5]benzo-                                                diazepin-5-one                                                343.                                                                              m-(trifluoromethyl)benzoic                                                                   1-[3-(trifluoromethyl)phenyl]-8-                                 acid hydrazide                                                                               chloro-6-phenyl-4H-s-triazolo-                                                 [4,3-a][1,5]benzodiazepin-5-one                               344.                                                                              o-chlorobenzoic acid                                                                         1-(2-chlorophenyl)-8-chloro-                                     hydrazide     6-phenyl-4H-s-triazolo[4,3-a][1,5]-                                            benzodiazepin-5-one                                           345.                                                                              p-methylbenzoic acid                                                                         1-(4-methylphenyl)-8-chloro-6-                                   hydrazide     phenyl-4H-s-triazolo[4,3-a][1,5]-                                              benzodiazepin-5-one                                           346.                                                                              m-methoxybenzoic acid                                                                        1-(3-methoxyphenyl)-8-chloro-6-                                  hydrazide     phenyl-4H-s-triazolo[4,3-a][1,5]-                                              benzodiazepin-5-one                                           347.                                                                              m-nitrobenzoic acid                                                                          1-(3-nitrophenyl)-8-chloro-6-                                    hydrazide     phenyl-4H-s-triazolo[4,3-a][1,5]-                                              benzodiazepin-5-one                                           348.                                                                              p-acetamidobenzoic                                                                           1-(4-acetamidophenyl)-8-chloro-6-                                acid hydrazide                                                                               phenyl-4H-s-triazolo[4,3-a][1,5]-                                              benzodiazepin-5-one                                           349.                                                                              o-(methylthio)benzoic                                                                        1-[2-(methylthio)phenyl]-8-chloro-                                             6-phenyl-4H-s-triazolo[4,3-a][1,5]-                                            benzodiazepin-5-one                                           350.                                                                              p-(methylsulfonyl)-                                                                          1-[4-(methylsulfonyl)phenyl]-8-                                  benzoic acid hydrazide                                                                       chloro-6-phenyl-4H-s-triazolo-                                                 [4,3-a][1,5]benzodiazepin-5-one                               __________________________________________________________________________

EXAMPLE 351

A group of experimental animals composed of rats, mice and monkeys are orally administered 1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one. The compound is administered at the following dosage levels: rats, 3.1 mg/kg; mice, 1 mg/kg; monkeys, 2.5 mg/kg. Ataxia is produced in all of the animals of the test group at the dosage levels indicated.

EXAMPLE 352

A group of rats is orally administered 1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one. The group is then subjected to the conflict test procedure described by Vogel et al., Psychopharmacologist, 21, 1 (1970). A tranquilizing effect is produced in all of the test animals.

EXAMPLE 353

A group of mice is orally administered 1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one at a dosage level of 12 mg/kg. At this dosage level the convulsant effect of 135 mg of subcutaneously administered pentylenetetrazole is antagonized in 50% of the animals.

EXAMPLE 354

In another test, the same group of mice is orally administered 26 mg/kg of the foregoing compound. This dosage level antagonizes the convulsant effect of 75 mg of intravenously administered strychnine in 50% of the test animals.

EXAMPLE 355

A group of mice are orally administered 30 mg/kg of 1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one. Food consumption is increased in the test animals by 100% compared to a group of control animals.

EXAMPLE 356 Preparation of capsule formulation

    ______________________________________                                         Ingredient           Milligrams per Capsule                                    ______________________________________                                         1-Methyl-8-chloro-6-phenyl-4H-s-                                               triazolo[4,3-a][1,5]benzodiazepin-5-one                                                             400                                                       Starch               80                                                        Magnesium stearate   5                                                         ______________________________________                                    

The active ingredient, starch and magnesium stearate are blended together. The mixture is used to fill hard shell capsules of a suitable size at a fill weight of 485 milligrams per capsule.

EXAMPLE 357 Preparation of tablet formulation

    ______________________________________                                         Ingredient           Milligrams per Tablet                                     ______________________________________                                         1-Methyl-8-chloro-6-phenyl-4H-s-                                               triazolo[4,3-a][1,5]benzodiazepin-5-one                                                             300                                                       Lactose              200                                                       Corn starch (for mix)                                                                               50                                                        Corn starch (for paste)                                                                             50                                                        Magnesium stearate   6                                                         ______________________________________                                    

The active ingredient, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in water at a ratio of 10 grams of corn starch per 80 milliliters of water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders. The wet granules are passed through a No. 8 screen and dried at 120° F. The dry granules are passed through a No. 16 screen. The mixture is lubricated with magnesium stearate and compressed into tablets in a suitable tableting machine. Each tablet contains 300 milligrams of active ingredient.

EXAMPLE 358 Preparation of oral syrup formulation

    ______________________________________                                         Ingredient               Amount                                                ______________________________________                                         1-Methyl-8-chloro-6-phenyl-4H-s-                                               triazolo[4,3-a][1,5]benzodiazepin-5-one                                                                 500 mg.                                               Sorbitol solution (70% N.F.)                                                                            40 ml.                                                Sodium benzoate          150 mg.                                               Sucaryl                  90 mg.                                                Saccharin                10 mg.                                                Red Dye (F.D. & Co. No. 2)                                                                              10 mg.                                                Cherry flavor            50 mg.                                                Distilled water   qs to  100 ml.                                               ______________________________________                                    

The sorbitol solution is added to 40 milliliters of distilled water and the active ingredient is suspended therein. The sucaryl, saccharin, sodium benzoate, flavor and dye are added and dissolved in the above solution. The volume is adjusted to 100 milliliters with distilled water.

Other ingredients may replace those listed in the above formulation. For example, a suspending agent such as bentonite magma, tragacanth, carboxymethylcellulose, or methylcellulose may be used. Phosphates, citrates or tartrates may be added as buffers. Preservatives may include the parabens, sorbic acid and the like and other flavors and dyes may be used in place of those listed above. 

What is claimed is:
 1. A compound of the formula ##STR30## wherein R¹ is 2-, 3- or 4-pyridyl,R² is H; alkyl of 1-4 carbons optionally substituted by amino, mono-lower alkyl amino, di-lower alkyl amino, cyclic imines of formula ##STR31## where D is methylene, oxygen or N-R¹⁰ and where p and q are the same or different and are the integers 1, 2, and 3 provided that p + q is at least 1; hydroxy; alkoxy of 1-6 carbons or ##STR32## where R⁵ is alkyl of 1-5 carbons optionally substituted by phenyl or X-substituted phenyl; or R⁵ is phenyl optionally substituted by 1 or more X-substituents, X and Y are the same or different and are hydrogen, F, Cl, Br, trifluoromethyl, alkyl of from 1-6 carbons, alkoxy of from 1-6 carbons, nitro, cyano, amino, alkanoylamino of 1-4 carbons, alkylthio of 1-6 carbons, alkylsulfinyl of 1-6 carbons or alkyl sulfonyl of 1-6 carbons; R¹⁰ is hydrogen, alkyl of 1-4 carbons or phenyl optionally substituted by X, wherein X is as defined above; and n is 0, 1 or
 2. 2. A compound according to claim 1 wherein R¹ is pyridyl, R² is hydrogen, X_(n) is hydrogen, chloro, trifluoromethyl, thiomethyl or nitro, each of the foregoing being in the 8-position and Y_(n) is fluoro or chloro in the 2'-position, or Y_(n) is difluoro in the 2'- and 6'-positions.
 3. A compound according to claim 1 wherein R² is hydrogen, methyl, dimethylaminomethyl or diethylaminomethyl.
 4. A compound according to claim 3 wherein R¹ is pyridyl, R² is hydrogen, methyl, dimethylaminomethyl, or diethylaminomethyl, X_(n) is chloro in the 8-position and Y_(n) is fluoro or chloro in the 2'-position or difluoro in the 2'-position and 6'-positions. 